CA2649043A1 - Azolecarboxamide derivative - Google Patents

Azolecarboxamide derivative Download PDF

Info

Publication number
CA2649043A1
CA2649043A1 CA002649043A CA2649043A CA2649043A1 CA 2649043 A1 CA2649043 A1 CA 2649043A1 CA 002649043 A CA002649043 A CA 002649043A CA 2649043 A CA2649043 A CA 2649043A CA 2649043 A1 CA2649043 A1 CA 2649043A1
Authority
CA
Canada
Prior art keywords
lower alkyl
esi
fab
aryl
substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CA002649043A
Other languages
French (fr)
Other versions
CA2649043C (en
Inventor
Keizo Sugasawa
Kenichi Kawaguchi
Takaho Matsuzawa
Ryushi Seo
Hironori Harada
Akira Suga
Tomoaki Abe
Hidenori Azami
Shunichiro Matsumoto
Takashi Shin
Masayuki Tanahashi
Toru Watanabe
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Astellas Pharma Inc
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Individual filed Critical Individual
Publication of CA2649043A1 publication Critical patent/CA2649043A1/en
Application granted granted Critical
Publication of CA2649043C publication Critical patent/CA2649043C/en
Expired - Fee Related legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/48—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Urology & Nephrology (AREA)
  • Rheumatology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Pain & Pain Management (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Thiazole And Isothizaole Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

[PROBLEMS] To provide a therapeutic or prophylactic agent for frequent urination/strong urge to urinate or incontinence associated with overactive bladder, a lower urinary tract disease accompanied by a lower urinary tract pain such as interstitial cystitis and chronic prostatitis or a disease accompanied by a pain, which acts based on excellent trkA receptor-inhibiting activity. [MEANS FOR SOLVING PROBLEMS] Disclosed is a novel azolecarboxamide derivative having an azole ring (e.g., a thiazole or oxazole ring) bound to a benzene, pyridine or pyrimidine ring through a carboxamide. It is confirmed that the azolecarboxamide derivative has a potent trkA receptor-inhibiting activity. It is found that the azolecarboxamide derivative can be used as a very efficient, safe therapeutic or prophylactic agent for a lower urinary tract disease or a disease accompanied by a pain.

Description

DESCRIPTION
AZOLECARBOXAMIDE DERIVATIVE
Technical Field The present invention relates to an azolecarboxamide derivative which is useful as a medicine, particularly as an agent for treating urinary frequency, urinary urgency, urinary incontinence, lower urinary tract pain, which are associated with various lower urinary tract diseases including overactive bladder, and various diseases accompanied by pain.

Background Art Overactive bladder refers to a clinical condition complaining urinary urgency regardless of incontinence, which is usually accompanied by urinary frequency and nocturia (Non-Patent Document 1) . Currently, an anticholinergic agent is mainly used for the treatment thereof, and certain therapeutic outcome has been shown.

However, it is known to cause side-effects such as dry mouth, constipation and blurred vision and it has been reported that the anticholinergic agent is difficult to be used for patients with prostatic hypertrophy or elderly patients because of a risk of urinary retention. In addition, there are patients showing no improvement with the anticholinergic agent. From the above facts, there is a great expectation for a drug with new mechanism of action against overactive bladder.

Nerve Growth Factor (NGF) is one of humoral factors named generically as a neurotrophic factor, which plays an important role in the development, differentiation and function maintenance of neurons in an organism. As the receptor of NGF, the high-affinity trkA receptor (receptor tyrosine kinase) and the low-affinity p75 receptor have been known. It has been reported that p75 binds to all of nerve growth factors, and is involved in apoptosis in the process of neuron development, but its role has not yet been fully elucidated. It has been known that NGF and trkA
receptor-knockout mice show the same phenotype (Non-Patent Document 1), and it is believed that a physiological action of NGF is exhibited mainly through the trkA receptor.

It has been known that the NGF level in bladder is high in a patient with overactive bladder or interstitial cystitis (Non-Patent Document 2), and it has been reported that an intravesical instillation of NGF reduces a bladder capacity of rat and that an inhibition of NGF improves urinary functions in the urinary frequency model rat (Non-Patent Document 3) . In addition, there have been reported that the inhibition of NGF improved urinary frequency or incontinence in patients with interstitial cystitis (Non-Patent Document 4), and thus it is believed that a trkA
receptor inhibitor is useful as an agent for treating urinary frequency/urinary urgency, and urinary incontinence which are associated with overactive bladder, and lower urinary tract diseases such as interstitial cystitis and prostatitis.
Moreover, a trkA receptor inhibitor has a different mechanism of action, and thus side effects which are characteristic to the anticholinergic agent are expected to be avoided and also an effect on patients who showed no improvement with the anticholinergic agent is expected. In addition, this agent is expected to show more potent effects on subjective symptoms by acting on sensory nerves.
Furthermore, this agent has been reported to exhibit an effect of improving morbid conditions without lowering the urinary pressure in the urinary frequency model rat (Non-Patent Document 5), and thus it is expected that this agent can be administered safely to a patient with prostatic hypertrophy or an elderly patient.

It has been also known that administration of NGF to human or rat induces pain, and that algesthesia in the trkA
knockout mice is lost. Consequently, NGF is believed to be strongly related in expression of pain. An NGF inhibition shows efficacy to the model animals with neuropathic pain or inflammatory pain, such as a model with pain induced by injury to sciatic nerve (Non-Patent Document 6) and a model with pain induced by damage to knee joint (Non-Patent Document 7), and the trkA receptor inhibitor is believed to be useful as an agent for treating a lower urinary tract disease accompanied by lower urinary tract pain and various kinds of pains such as an osteoarthritis.

As the compound mentioned above, there have been known an indolocarbazole derivative (Non-Patent Document 8), a pyrrolocarbazole derivative (Patent Document 1), a pyrazolone derivative (Patent Document 2), an oxyindole derivative (Patent Document 3 and 4), an azaoxyindole derivative (Patent Document 5), a pyrazolyl condensed ring compound (Patent Document 6), a pyrazole derivative (Patent Document 7 and 8), a tricyclic derivative (Patent Document 9) and ALE-0540 (Patent Document 10).

In addition to the above Non-Patent Document 8 and Patent Documents 1 to 10, as the compound having relatively similar structure, a compound represented by the following general formula (XV) is disclosed as a c-fms kinase inhibitor in Patent Document 11. However, a trkA receptor-inhibitory activity in the present invention is not mentioned at all. Furthermore, in this publication, there is no specific disclosure in Examples and so forth as for the compound having thiazole or oxazole skeleton wherein 2-position is substituted.

[Chem. 12]

R~
N,X'W
AI
N~RZ (XV) (In the formula, A is phenyl, naphthyl, or biphenyl which may respectively be substituted; or a 5 to 7-membered aromatic monoheterocyclic group or a 8 to 10-membered aromatic biheterocyclic group which may respectively be substituted and have 1 to 4 N, 0, or S; R1 is -H, aryl, or the like; X is -CO-, -C(=NH)-, -CS-, or the like; R2 and R3 are each independently -H, C1_6 alkyl, aryl, cycloalkyl, or the like, while R2 and R3 may, together with the nitrogen to which R2 and R3 are bonded, form a 5 to 7-membered heterocyclic group or aromatic heterocyclic group, and the heterocyclic group may be substituted and contain 1 to 3 N, O or S; W is phenyl, naphthyl or biphenyl which may respectively be substituted, or a 5 or 6-membered monocyclic or 8 to 10-membered bicyclic heterocyclic group or aromatic heterocyclic ring, which may respectively be substituted and contain 1 to 4 N, 0 or S. For details, refer to the publication).

Non-Patent Document 1: `Reviews in the Neurosciences', (England), 1997, vol 8, p.13 to 27 Non-Patent Document 2: `British Journal of Urology', (England); 1997, vol 79, p.572 to 7 Non-Patent Document 3: `Neuroscience', (U.S.A.), 1997, vol. 78, No. 2, p.449 to 59 Non-Patent Document 4: `General Outline preliminarily described for the 99th American Urology Association', (San Francisco), 2004, #363 Non-Patent Document 5: `The Journal of Urology', (U.S.A.), 2005, vol 173, p.1016 to 21 Non-Patent Document 6: `Pain', (U.S.A.), 1999, vol 81, p.245 to 55 Non-Patent Document 7: `Pain', (U.S.A.), 2005, vol 116, p.8 to 16 Non-Patent Document 8: `Cancer Research', 1999, vol 59, p.2395 to 2401 Patent Document 1: International Publication pamphlet Patent Document 2: International Publication pamphlet Patent Document 3: International Publication pamphlet Patent Document 4: International Publication pamphlet Patent Document 5: International Publication pamphlet Patent Document 6: Japan Patent Application Publication 2003-231687 Patent Document 7: International Publication pamphlet Patent Document 8: International Publication pamphlet Patent Document 9: International Publication pamphlet Patent Document 10: International Publication pamphlet W001/78698 Patent Document 11: International Publication pamphlet W02004/096795 DISCLOSURE OF THE INVENTION

PROBLEMS TO BE SOLVED BY THE INVENTION

As described above, existing agents for treating urinary frequency, urinary urgency, urinary incontinence which are associated with overactive bladder, and various lower urinary tract diseases accompanied by pain in the lower urinary tract such as interstitial cystitis and chronic prostatitis, are not satisfactory in the points of efficacy, safety, etc. Thus, an agent for treating lower urinary tract disease which is excellent in efficacy and safety has been demanded.

MEANS FOR SOLVING THE PROBLEMS

As described above, a trkA receptor inhibitor is expected to be a highly safe therapeutic agent with few side effects such as dry mouth and urinary retention, for a lower urinary tract disease. The inventors of the present invention made extensive studies on a compound having a trkA receptor-inhibitory activity in order to provide a novel compound useful for treating a lower urinary tract disease and so forth. As a result, they found that an azolecarboxamide derivative represented by the following general formula (I) exhibits potent trkA receptor-inhibitory activity, thus they completed the invention.
That is, the present invention relates to a novel azolecarboxamide derivative or a salt thereof, the derivative represented by the following general formula (I) :

[Chem. 13]
O
A tv N
H

Q (I) (In the formula, symbols have the following meanings;
X: S or 0, A: phenylene which may be substituted, pyridinediyl which may be substituted, pyrimidinediyl which may be substituted, thiophenediyl which may be substituted, pyrazolediyl which may be substituted, or pyridonediyl which may be substituted, Q: a monocyclic or bicyclic alicyclic nitrogen-containing heterocyclic group which may be substituted, Rl: halogen, lower alkylcarbonyl, C1-C7 alkyl which may be substituted, lower cycloalkyl which may be substituted, lower alkoxy which may be substituted, aryl which may be substituted, heteroaryl which may be substituted, a group represented by the general formula (II), the general formula (III), or the general formula (IV):

[Chem. 14]

Rla RI\
-N\ 1b -N Y1 C y2 R

(I I) (I I I) (I V) Rla and Rlb: each independently -H, lower alkyl which may be substituted, lower cycloalkyl, a saturated heterocyclic group which may be substituted, lower alkylcarbonyl, lower alkoxycarbonyl, aryl, or heteroaryl, Rlc: -H or lower alkyl, Y1: lower alkylene which may be substituted in which -0-, -S-, -SO-, -SO2-, or -N (-Rld) - may be contained between carbons thereof, Rla: -H, lower alkyl, lower alkylcarbonyl, lower alkoxycarbonyl, or aryl-lower alkyl, YZ: lower alkylene in which -0-, -S-, -SO2-, -N (-Rle) -, -N (-CO-Rlf) -, -N (-CO-NH-Rlg) -, -N (-CS-NH-Rlg) -, or -N(-S02-Rlh)- may be contained between carbons thereof, Rle: -H or lower alkyl which may be substituted, Rlf: lower alkyl which may be substituted, lower cycloalkyl, lower alkoxy, aryl which may be substituted, heteroaryl which may be substituted, or aryl-lower alkenyl, Rlg: -H, lower alkyl, aryl, or aryl-lower alkyl, Rlh: lower alkyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl which may be substituted, heteroaryl, or aryl-lower alkyl, R2 is -H, halogen, or a nitrogen-containing saturated heterocyclic group. The same shall be applied hereinafter).

EFFECTS OF THE INVENTION

The compound of the present invention has a potent trkA receptor-inhibitory activity, urinary symptom-improving action, and analgesic action, and thus is useful as an agent for treating or preventing, for example, urinary frequency, urinary urgency, urinary incontinence which are associated with various lower urinary tract diseases including overactive bladder, and various lower urinary tract diseases accompanied by pain in the lower urinary tract such as interstitial cystitis and chronic prostatitis, as well as various diseases accompanied by pain.
Since the compound of the present invention has different mechanism of action from the anticholinergic agent, an effect on patients who showed no improvement with the anticholinergic agent can be expected, and it is expected to be served as a very safe agent for treating a lower urinary tract disease by avoiding side effects which are characteristic to the anticholinergic agent.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in more detail.

As used in the definition of the general formulae in the present specification, the term "lower" means a linear or branched carbon chain having 1 to 6 carbon atoms (hereinafter simply referred to as C1-6), unless otherwise specifically mentioned. Accordingly, the "lower alkyl" is C1-6 alkyl, preferably linear alkyl such as methyl, ethyl, n-propyl, and n-butyl groups, and a branched alkyl such as isopropyl, isobutyl, tert-butyl, and neopentyl groups.

More preferred is C1-4 alkyl, and particularly preferred are methyl, ethyl, n-propyl, isopropyl, and tert-butyl groups.
The "lower alkylene" is a divalent group of C1-6 alkyl, preferably C1_3 alkylene, such as methylene, ethylene, methyl methylene, ethyl methylene, and trimethylene.

The "lower alkenyl" means C2-6 alkenyl, preferred are vinyl and allyl, and particularly preferred is allyl.

The "lower alkoxy" means -0-lower alkyl, preferred is C1-4 alkoxy, and particularly preferred are methoxy, ethoxy, and tert-butoxy.

The "halogen" means F, Cl, Br, and I. The "halogeno-lower alkyl" means C1-6 alkyl substituted with one or more halogen, preferred is C1-6 alkyl substituted with one or more F or Cl, and more preferred are chloropropyl, fluoroethyl, trifluoromethyl, trifluoroethyl, and trifluoropropyl groups.

The "cycloalkyl" is a C3-10 saturated hydrocarbon ring group, which may have bridge(s). Preferred is C3-8 cycloalkyl, and particularly preferred are cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl groups.

The "aryl" is a C6-14 mono- to tricyclic aromatic hydrocarbon ring group, preferred are phenyl and naphthyl groups. More preferred is phenyl. The aryl may be condensed with monocyclic, oxygen-containing, saturated heterocyclic or monocyclic cycloalkyl. The "aryl-lower alkyl", the "aryl-lower alkenyl", the "aryloxy", the "arylamino", and the "arylcarbonyl" represent "lower alkyl substituted with aryl", "lower alkenyl substituted with aryl", "oxy substituted with aryl", "amino substituted with aryl", and "carbonyl substituted with aryl", respectively.
The "heteroaryl" collectively means a 5 to 8-membered, preferably 5- to 6-membered monocyclic aromatic ring group (monocyclic heteroaryl) each of which has 1 to 3 heteroatom(s) selected from 0, S, and N, or a bicyclic or tricyclic heteroaryl having the monocyclic heteroaryl groups condensed with each other, having a benzene ring condensed with the monocyclic heteroaryl group, or having a benzene ring condensed with the heterocyclic group.
Preferable examples of the monocyclic heteroaryl include pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, triazolyl, thienyl, furyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isooxazolyl, and oxadiazolyl groups, and more preferably pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, thienyl, and furyl groups. Preferable examples of the bicyclic heteroaryl include dihydrobenzofuranyl.

In the"heteroaryl", the ring atom S may be oxidized to form an oxide or dioxide, and N may be oxidized to form an oxide. The "heteroaryl-lower alkyl" means "lower alkyl substituted with heteroaryl".

The "saturated heterocyclic group" means a 4- to 8-membered, preferably 5- to 6-membered saturated heterocyclic group containing one heteroatom of N or 0, and a 5- to 8-membered saturated heterocyclic group containing one N atom, and one heteroatom selected from N, 0, and S.
Preferred are azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, piperazinyl, diazepanyl, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, oxazepanyl, and thiomorpholinyl groups.

In the "saturated heterocycle", the ring atom S may be oxidized to form an oxide or dioxide, and N may be oxidized to form an oxide.

The "alicyclic heterocyclic group" means a corresponding heterocyclic group having double bonds in the above-mentioned saturated heterocyclic group or its structure. Preferred are azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, piperazinyl, diazepanyl, tetrahydrofuryl, tetrahydropyranyl, morpholinyl, oxazepanyl, thiomorpholinyl, pyrrolinyl, and tetrahydropyridyl groups.

The "monocyclic or bicyclic, alicyclic nitrogen-containing heterocyclic group" means a saturated or partially unsaturated 4- to 8-membered, preferably 5- to 6-membered monocyclic nitrogen-containing heterocyclic group, or a 4- to 8-membered, preferably 5- to 6-membered nitrogen-containing heterocyclic group having one bridge.
More preferred are azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, piperazinyl, diazepanyl, morpholinyl, thiomorpholinyl, 2,5-diazabicycloheptyl, and tetrahydropyridyl groups.

Preferred embodiments in the compound of the present invention represented by the general formula (I) are described in the following.

1) The compound, wherein X is S or 0, and the general formula (I) is represented by the following formula:

[Chem. 15]

O O
A A N
H I ~- R' H R1 Q Q
(I a) (Ib) Q or Q
(I c) (I d) 2) The compound as described in 1), wherein A is a divalent group represented by the following formula:

A:
[Chem. 16]

N

N Ra R R5 N R-N S ql-or (The symbols in the formula have the following meanings:

R3: -H, halogen, lower alkyl, cyano, cyano lower alkyl, hydroxy-lower alkyl, lower alkoxy, halogeno-lower alkoxy, lower alkoxy-lower alkyl, lower alkenyl, cyano lower alkenyl, carboxy, carbamoyl, lower alkoxy-carbonyl, carboxy-lower alkyl, lower alkoxy-carbonyl-lower alkyl, carbamoyl-lower alkyl, lower alkyl-aminocarbonyl-lower alkyl, lower alkyl-sulfonyl, aminosulfonyl, or lower alkylsulfinyl, R4: -H, halogen, or lower alkoxy, R3 and R4 in combination may be bridged as -0-lower alkylene, R5: -H or halogen, R 6 : -H or lower alkyl. The same shall be applied hereinafter.) 3) More preferably, the compound as described in 2), wherein A is a divalent group represented by the following formula:

[Chem. 17]

R25 R2a N
R2a R2a N /
, ~ .

R23 R26 2s N / \ I R _N S

N ~ N R

or 4) Even more preferably, the compound as described in 3), wherein A is as described in 3) and the symbols in the formula have the following meanings:

R23: -H, fluoro, chloro, bromo, methyl, ethyl, vinyl, cyano, cyanomethyl, cyanoethyl, cyanovinyl, hydroxymethyl, methoxy, difluoromethoxy, trifluoromethoxy, methoxymethyl, methoxycarbonyl, carboxy, carbamoyl, mesyl, aminosulfonyl, methylsulfinyl, or -Alk-CO-R23a~
-Alk-: methylene or ethylene, R23a: hydroxy, amino, tert-butylamino, methoxy, or ethoxy, R24: -H, fluoro, chloro, bromo, or methoxy, R23 and R24 in combination may be bridged as a -0-ethylene, R25: -H or bromo, R26: -H or methyl).

5) The compound as described in 2), wherein Q is a cyclic group selected from the groups represented by the general formulae (V), (VI), (VII), (VIII), and (IX):
[Chem. 18]

VR7 v R~ O_+ vR~

v2 ~Rs U2~R8 V2 Ra (V) (VI) (VI I) R 7 R7 va N-R9 N Rs V2 _>~ R$ 2 R v (V I I I) (I X) (The symbols in the formula have the following meanings:

V1, VZ: each independently C1_3 alkylene, V3: methylene or ethylene, W: -CH (-R9) -, -N (-R9) -, -0-, -S-, -SO-, or -SO2-, R' and R8: each independently -H, halogen, hydroxy, lower alkyl, hydroxy-lower alkyl, carboxy, lower alkoxycarbonyl, lower alkylcarbonyloxy, carbamoyl, aryl, aryl-lower alkyl, a saturated heterocyclic group which may be substituted with lower alkyl, or an -Alk-saturated heterocyclic group, -Alk-: lower alkylene, and two of R7, R8, and R9 in combination may be bridged as a lower alkylene, R7 and R8 may be substituted with the same carbon atoms, or in combination may form an oxo group, or a nitrogen-containing saturated heterocyclic group having spiro bonds, wherein the nitrogen-containing saturated heterocyclic group may be substituted with a lower alkyl or oxo group, R9: -H, lower alkyl, cyano, hydroxy, lower alkoxy, lower alkenyl, lower alkoxycarbonyl-lower alkenyl, lower alkylsulfonyl, -Alk-R9a, -CO-Rgb, -Alk-CO-R9b, -CO-Alk-R9c , -NR9dR9e, aryl, aryloxy, or a saturated heterocyclic group, wherein the saturated heterocyclic group may be substituted with a lower alkyl, hydroxy, or oxo group, -Alk-: lower alkylene, R9a: cyano, hydroxy, lower alkoxy, mono- or dihydroxy lower alkyl, aryl, aryloxy, arylcarbonyloxy, amino which may be substituted with lower alkyl, lower alkoxy-carbonylamino, heteroaryl, or saturated heterocyclic group, wherein the heteroaryl may be substituted with a lower alkyl or oxo group, and the saturated heterocyclic group may be substituted with a lower alkyl group, R9b: lower alkyl, hydroxy, lower alkoxy, -NR9fRgg or alicyclic heterocyclic group, wherein the alicyclic heterocyclic group may be substituted with lower alkyl, hydroxy, carboxy, lower alkoxycarbonyl, mono- or di-lower alkylamino, a saturated heterocyclic group, or an -Alk-saturated heterocyclic group, -Alk-: lower alkylene, R9f and R99: each independently -H, lower alkyl, hydroxy-lower alkyl, lower cycloalkyl which may be substituted with amino, lower alkoxy-lower alkyl, mono- or di-lower alkyl-amino-lower alkyl, lower alkylsulfonyl, heteroaryl, a saturated heterocyclic group, wherein the saturated heterocyclic group may be substituted with lower alkyl or aryl-lower alkyl, or an -Alk-saturated heterocyclic group, -Alk-: lower alkylene, R9c : lower alkoxy, lower alkylcarbonyloxy or saturated heterocyclic group, wherein the saturated heterocyclic group may be substituted with a lower alkyl or oxo group, and R9d and R9e: each independently -H, lower alkyl, lower alkylcarbonyl, or carbamoyl-lower alkyl).

6) More preferably, the compound as described in 5), wherein Q is a cyclic group represented by the following formula:

[Chem. 19]

N N N Rzs Rz7 1 Rzs Rz7 (~ 1 Rzs Rz7 R2s zE
T w_ C7- R

zs~ zs I
, zs Rzs R Rzs R R

N N N N O-JN+
Rzs (R27 Rzs K Nzs Rzs N29 Rz9 Rzs R R
I ~ N N
N
29 ~

29 R29 Rzs R ` , .

N N O~N
N N N C J
Co ~ CS) (S) CS" S 11 O O d O or O

(The symbols in the formula have the following meanings:

R 27 and R28: each independently -H, fluoro, hydroxy, oxo, methyl, hydroxymethyl, carboxy, carbamoyl, acetoxy, methoxycarbonyl, phenyl, benzyl, pyrrolidinylmethyl, or piperidinyl which may be substituted with methyl, R 27 and R28 in combination may be bonded with the same Q ring-constituting carbon atom to form a pyrrolidine ring which may be substituted with methyl and oxo, and thus may have a spiro bond.

R29: -H, hydroxy, cyano, methyl, ethyl, isopropyl, isopentyl, allyl, methoxy, methoxycarbonylallyl, ethoxycarbonylallyl, phenyl, phenoxy, piperidinyl which may be substituted with a methyl group, piperazinyl which may be substituted with a methyl group or an oxo group, morpholinyl, methylsulfonyl, tetrahydrofuryl which may be substituted with hydroxy, -Alk-R29a, -CO-R29b, -Alk-CO-R29b, -CO-Alk-R29c, or -NR29aR29e~

-Alk-: methylene, ethylene, methylmethylene, trimethylene, tetramethylene, or pentamethylene, R29a: methoxy, cyano, hydroxy, phenyl, phenoxy, benzoyloxy, pyridyl, thiazolyl, oxazolyl, oxadiazolyl, triazolyl which may be substituted with oxo, imidazolyl which may be substituted with methyl, pyrrolidinyl which may be substituted with methyl, piperidinyl which may be substituted with methyl, morpholinyl, oxazepanyl, 1,2-dihydroxyethyl, 1-hydroxypropyl, amino, dimethylamino, diethylamino, or tert-butoxycarbonylamino, R29b: methyl, hydroxy, methoxy, ethoxy, butoxy, pyrrolidinyl which may have a substituent selected from the following Group G5-1, pyrrolinyl, piperidinyl which may have a substituent selected from the following Group G5-2, piperazinyl which may have a substituent selected from the following Group G5-3r diazepanyl which may be substituted with methyl, morpholinyl, tetrahydropyranyl, or -NR29tR29g, R29f: -H, methyl, ethyl, hydroxyethyl, methoxyethyl, tetrahydropyranyl, morpholinylethyl, dimethylaminoethyl, mesyl, pyridyl, cyclohexyl which may be substituted with amino, piperidinyl which may be substituted with methyl, or pyrrolidinyl which may have a substituent selected from the following Group Gs-4, R29g: -H, methyl, or ethyl, Group G5-1: hydroxy, methyl, dimethylamino, and pyrrolidinylmethyl, Group G5-2: methyl, carboxy, ethoxycarbonyl, and pyrrolidinyl, Group G5-3: methyl and propyl, Group G5_4: methyl and benzyl, R29c: methoxy, acetoxy, pyrrolidinyl, piperazinyl which may be substituted with methyl, morpholinyl, or thiomorpholinyl which may be substituted with oxo, R29d and R29e: each independently -H, methyl, ethyl, acetyl, or carbamoylmethyl).

7) The compound as described in 5), wherein R1 is represented by the following formula:

R1: halogen, lower alkylcarbonyl, lower cycloalkyl which may be substituted with hydroxy, or lower alkoxy which may be substituted with lower alkoxy, C1-C7 alkyl which may have a substituent selected from the following Group G6_1r aryl, heteroaryl, a group represented by the general formula (X), (XI), (XII), (XIII), or (XIV), wherein the aryl and the heteroaryl may have one or two substituents selected from the following Group G6-2, and the two substituents in combination may form a cyclic structure, Group G6-1: hydroxy, lower alkoxy, N-lower alkyl-N-lower alkoxy-lower alkyl-amino, mono- or di-lower alkyl amino, a saturated heterocyclic group, aryl, and aryloxy, wherein the aryl or the aryloxy may be substituted with halogen or halogeno-lower alkyl, Group G6-2: halogen, hydroxy, oxo, lower alkyl, halogeno-lower alkyl, lower alkoxy, cyano, carboxy, carbamoyl , and -NR11R1j , R1i and R1j: each independently -H, lower alkyl, lower alkoxy-lower alkyl, or lower alkoxycarbonyl, [Chem. 20]

/R1p /(CH2) -~ ~R1r R1 t (CH2)m\
_N~ 1 _N ~CY3 N_R1u R q R15 /
(CH2)n (X) (X I ) (X I I ) R1v N (CH2) O D (X I I I) (X I V) Rlp, R1q: each independently -H, lower cycloalkyl, lower alkylcarbonyl, lower alkoxycarbonyl, aryl, heteroaryl, a saturated heterocyclic group, or lower alkyl which may have a substituent selected from the following Group G6_3r wherein the saturated heterocyclic group may have a substituent selected from the group consisting of lower alkyl which may be substituted with one or two aryl, and aryl-lower alkoxycarbonyl, Group G6-3: halogen, hydroxy, cyano, lower alkoxy, lower alkoxy-lower alkoxy, aryl, heteroaryl, a saturated heterocyclic group, carboxy, lower alkoxycarbonyl, lower alkylsulfanyl, lower alkylsulfinyl, lower alkylsulfonyl, carbamoyl which may be substituted with lower alkyl, and -NR1xR11, Rlk and R'-l: each independently -H, lower alkyl, lower alkylcarbonyl, lower alkoxycarbonyl, or lower alkylsulfonyl, k: 0, 1, or 2, Y3: single bond, -CH2-, -0-, -N (-R1 m) -, -S-, -SO-, or -SOZ-Rlm: -H, lower alkyl, lower alkylcarbonyl, lower alkoxycarbonyl, or aryl-lower alkyl, Rlr, Rls : each independently -H, halogen, hydroxy, lower alkyl, lower alkoxy, hydroxy-lower alkyl, lower alkoxy-lower alkyl, lower alkylcarbonyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, mono- or di-lower alkyl-amino-lower alkyl, aryl, or -CO-NH-Alk-Rln, -Alk-: lower alkylene, R1n: hydroxy or a saturated heterocyclic group, wherein Rlr and Rls in combination may be bridged as a lower alkylene, and Rlr and Rls may be substituted with the same carbon atom, and may form an oxo group, m=0, 1, or 2, and n=1, 2, 3, or 4, preferably, m=0, 1, or 2, and n= 2 or 3, more preferably, in a case of m=0, n=3, in a case of m=1, n=3, and in a case of m=2, n=2, Rit: -H or lower alkyl, Rlu: -H, lower alkyl, -Alk-Rl6', -CO-RlX, -S02-R11', or -CS-NH-RlZ, -Alk-: lower alkylene, RlW: lower cycloalkyl, lower alkoxy, carboxy, carbamoyl, a saturated heterocyclic group, aryl, or heteroaryl, wherein the aryl may have a substituent selected from the group consisting of lower alkyl, lower alkoxy, and carboxy groups, RlX: lower alkyl, lower cycloalkyl, hydroxy-lower alkyl, lower alkoxy, lower alkoxy-lower alkyl, amino, lower alkyl-amino, arylamino, aryl-lower alkyl amino, mono- or di-lower alkyl-amino-lower alkyl, aryl, aryl-lower alkyl which may be substituted with halogen, aryl-lower alkenyl, heteroaryl, heteroaryl-lower alkyl, wherein the aryl or the heteroaryl may have a substituent selected from the group consisting of halogen, lower alkyl, lower alkoxy, and aryl, R1Y: lower alkyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl, aryl-lower alkyl, heteroaryl, wherein the aryl may have a substituent selected from the group consisting of halogen and aryl, Rlz: lower alkyl, aryl, aryl-lower alkyl, Rlv: -H or lower alkoxycarbonyl, Y4: -0-, -S- or -S02-, h: 0 or 1).

8) More preferably, the compound as described in 7), wherein R' is a group represented by the following (a) to (1):

(a) bromo, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, cyclopentyl, cyclohexyl which may be substituted with hydroxy, acetyl, or methoxyethoxy, (b) lower alkyl having a substituent selected from the following Group G7-1r Group G7-1: hydroxy, methoxy, propoxy, phenoxy which may be substituted with butyl, phenyl which may be substituted with chloro or trifluoro methyl, morpholinyl, dimethylamino, and methoxyethyl(methyl)amino, (c) phenyl, pyridyl, or pyrazolyl, wherein these groups may be substituted with one or two groups selected from the following Group G7_2r Group G7-2: fluoro, chloro, bromo, hydroxy, oxo, methyl, trifluoromethyl, methoxy, cyano, carboxy, carbamoyl, amino, methylamino, dimethylamino, methoxyethyl(methyl)amino, and tert-butoxycarbonylamino, (d) pyrimidinyl, pyrazinyl, pyridazinyl which may be substituted with methoxy, oxodihydropyridyl, pyrrolyl, furyl, thienyl, or dihydrobenzofuranyl, ( e ) -NR11pRllq R11p: -H, methyl, ethyl, propyl, isopropyl, cyclobutyl, trifluoromethyl, or methoxyethyl, Rllq: -H, cyclopropyl, cyclobutyl, acetyl, tert-butoxycarbonyl, phenyl, pyridyl, tetrahydropyranyl, tetrahydrofuryl, oxetanyl, pyrrolidinyl, methylpyrrolidinyl, benzyloxycarbonylpyrrolidinyl, diphenylmethylazetidinyl, or Cl-C4 alkyl which may have a substituent selected from the following Group G7-3, Group G7-3: fluoro, chloro, hydroxy, cyano, methoxy, ethoxy, methoxyethoxy, amino, methylamino, dimethylamino, acetylamino, mesylamino, tert-butoxycarbonylamino, carboxy, carbamoyl, dimethylaminocarbonyl, methoxycarbonyl, phenyl, pyridyl, furyl, tetrahydrofuryl, methylthio, methylsulfinyl, and mesyl, (f) 4-morpholinyl, wherein the morpholinyl may have a substituent selected from the following Group G7-4, Group G7-4: methyl, hydroxymethyl, methoxymethyl, and dimethylaminomethyl, (g) 1-piperazinyl or 1-diazepanyl, wherein these groups may be substituted with a group selected from the following Group G7-5for a nitrogen atom, and may have a group selected from the following Group G7-6, Group G7-5: methyl, propyl, acetyl, benzyl, or tert-butoxycarbonyl, Group G7-6: fluoro, hydroxy, hydroxymethyl, methoxy, methoxymethyl, oxo, methylamino, or phenyl, (h) 1-piperidinyl, wherein the piperidinyl may be substituted with one or two group selected from the following G7-7, Group G7-7: fluoro, hydroxy, hydroxymethyl, methoxy, ethoxy, acetyloxy, oxo, carboxy, carbamoyl, ethoxycarbonyl, hydroxypropylcarbamoyl, or tetrahydrofurylmethylcarbamoyl, (i) 1-pyrrolidinyl or 1-azetidinyl wherein these groups may be substituted with one or two groups selected from the following Group G7-8r Group G7-8: fluoro, hydroxy, hydroxymethyl, methoxy, methoxymethyl, oxo, methylamino, or phenyl, (j) 3-morpholinyl, 3-piperidinyl, 2-pyrrolidinyl, or 3-pyrrolidinyl, wherein these groups may be substituted with a group selected the following G7-9 for a nitrogen atom, Group G7_9: acetyl, tert-butoxycarbonyl, or benzyl, (k) 4-oxazepanyl, 4-thiomorpholinyl, 1-oxothiomorpholin-4-yl, 1,1-dioxothiomorpholin-4-yl, 2,5-diazabicycloheptan-l-yl, 2-oxa-5-azabicyclo[2.2.1]heptan-5-yl, tetrahydrofuryl, tetrahydropyranyl, thiacyclohexyl, or 1,1-dioxothiacyclohexyl, (1) a group represented by the following formula:
[Chem. 21]

R21 t R21 t 0 N-AIk-R21w N'J~' R 21x R21 t R21 t S 21 z O
NSR21Y N~N~ R
-IC --IC

p or (The symbols in the formula have the following meanings:
R21t : -H or methyl, -Alk-: methylene, ethylene, trimethylene, tetramethylene, pentamethylene, methyltrimethylene, R21": -H, cyclopropyl, methoxy, carboxy, carbamoyl, tetrahydrofuryl, pyridyl, or phenyl, wherein the phenyl may have a substituent selected from the group consisting of methyl, methoxy, and carboxy, R21x: methyl, ethyl, propyl, butyl, pentyl, isopropyl, ethylpropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolyl which may be substituted with methyl, pyridyl, pyridazinyl, pyrimidinyl, thienyl, phenyl, tert-butoxy, amino, isopropylamino, phenylamino or benzylamino, phenylvinyl, phenylpropenyl, or -Alk31X-R31X, wherein the phenyl may have a substituent selected from the group consisting of fluoro, methyl, methoxy, and phenyl, -Alk31X-: methylene, ethylene, trimethylene, or tetramethylene, R31X: phenyl or pyridyl, each of which may be substituted with hydroxy, methoxy, dimethylamino, or fluoro, R21y: methyl, ethyl, propyl, butyl, isopropyl, cyclopropyl, cyclohexyl, cyclohexylmethyl, phenyl, benzyl, phenylethyl, or thienyl, wherein the phenyl may have a substituent selected from the group consisting of fluoro and phenyl, RZ1z: methyl, isopropyl, phenyl, or benzyl).

9) The compound as described in 7), wherein R2 is a group represented by the following:

R2: -H, halogen, or a nitrogen-containing saturated heterocyclic group.
10) More preferably, the compound as described in 9), wherein R2 is as follows:

Rz: -H, bromo, or a pyrrolidinyl group.

In the specification, the substituent acceptable by the term "may be substituted" may be any of the groups that are usually used in the technical field as a substituent of a respective group, and each of the groups may have at least one substituent.

In A of the general formula (I), examples of the substituent of the "phenylene which may be substituted, pyridinediyl which may be substituted, or pyrimidinediyl which may be substituted" include halogen, lower alkyl, cyano, cyano-lower alkyl, hydroxy-lower alkyl, lower alkoxy, halogeno-lower alkoxy, lower alkoxy-lower alkyl, lower alkenyl, cyano-lower alkenyl, carboxy, carbamoyl, lower alkoxycarbonyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl, lower alkylaminocarbonyl-lower alkyl, lower alkylsulfonyl, aminosulfonyl, or lower alkylsulfinyl.

Examples of the substituent of the "thiophenediyl which may be substituted, pyrazoldiyl which may be substituted, or pyridonediyl which may be substituted" in A

of the general formula (I), in which two substituents in combination may be bridged as -0-lower alkylene, include halogen and lower alkyl.

Examples of the substituent of the "monocyclic or bicyclic, alicyclic nitrogen-containing heterocyclic group which may be substituted" in Q of the general formula (I) include halogen, hydroxy, oxo, cyano, lower alkyl, lower alkenyl, lower alkoxycarbonyl-lower alkenyl, lower alkylcarbonyloxy, lower alkylsulfonyl, aryl, aryloxy, a saturated heterocyclic group, and groups represented by -Alk-R9a, -CO-R9b, -Alk-CO-R9b, -CO-Alk-R9 , and -NR9dR9e.
Here, the saturated heterocyclic group may be substituted with a lower alkyl, hydroxy, or oxo group, or may have a spiro bond.

The symbols in the formula have the following meanings:

-Alk-: lower alkylene, R9a: cyano, hydroxy, lower alkoxy, mono- or dihydroxy-lower alkyl, aryl, aryloxy, arylcarbonyloxy, amino which may be substituted with lower alkyl, heteroaryl, or a saturated heterocyclic group, wherein the heteroaryl may be substituted with a lower alkyl or oxo group, and the saturated heterocyclic group may be substituted with lower alkyl, R9b: lower alkyl, hydroxy, lower alkoxy, an alicyclic heterocyclic group, or -NR9fR9g, wherein the alicyclic heterocyclic group may be substituted with lower alkyl, hydroxy, carboxy, lower alkoxycarbonyl, mono- or di-lower alkylamino, a saturated heterocyclic group, or an -Alk-saturated heterocyclic group, -Alk-: lower alkylene, R9f and R99: each independently -H, lower alkyl, hydroxy-lower alkyl, lower cycloalkyl which may be substituted with amino, lower alkoxy-lower alkyl, mono- or di-lower alkyl-amino-lower alkyl, lower alkylsulfonyl, heteroaryl, a saturated heterocyclic group, wherein the saturated heterocyclic group may be substituted with lower alkyl or aryl-lower alkyl, or an -Alk-saturated heterocyclic group, -Alk-: lower alkylene, R9c : lower alkoxy, lower alkylcarbonyloxy, or a saturated heterocyclic group, wherein the saturated heterocyclic group may be substituted with lower alkyl or oxo, R9d and R9e: each independently -H, lower alkyl, lower alkylcarbonyl, or carbamoyl-lower alkyl).

Examples of the substituent of the "C1-C7 alkyl which may be substituted" in R' of the general formula (I) include hydroxy, lower alkoxy, N-lower alkyl-N-lower alkoxy lower alkyl-amino, mono- or di-lower alkylamino, a saturated heterocyclic group, aryl, and aryloxy.

Here, the aryl or aryloxy may be substituted with halogen or halogeno-lower alkyl.

Examples of the substituent of the "lower cycloalkyl which may be substituted" in R' of the general formula (I) include hydroxy.

Examples of the substituent of the "lower alkoxy which may be substituted" in R' of the general formula (I) include lower alkoxy.

Examples of the substituent of the "aryl which may be substituted" and the "heteroaryl which may be substituted"
in Rl of the general formula (I) include halogen, hydroxy, oxo, lower alkyl, halogeno-lower alkyl, lower alkoxy, cyano, carboxy, carbamoyl, and -NR11R1j The symbols in the formula have the following meanings:

R1i and R1~: each independently -H, lower alkyl, lower alkoxy-lower alkyl, or lower alkoxycarbonyl).

Examples of the substituent of the "lower alkyl which may be substituted" in Rla and Rlb in the general formula (II) include halogen, hydroxy, cyano, lower alkoxy, lower alkoxy-lower alkoxy, aryl, heteroaryl, a saturated heterocyclic group, carboxy, lower alkoxycarbonyl, lower alkylsulfanyl, lower alkylsulfinyl, lower alkylsulfonyl, carbamoyl which may be substituted with lower alkyl, and -NR1xR11 The symbols in the formula have the following meanings:

Rlk and R11: each independently -H, lower alkyl, lower alkylcarbonyl, lower alkoxycarbonyl or lower alkylsulfonyl).

Examples of the substituent of the "saturated heterocyclic group which may be substituted" in Rla and Rlb in the general formula (II) include lower alkyl which may be substituted with aryl, and aryl-lower alkoxycarbonyl.

Examples of the substituent of the "lower alkylene which may be substituted" in Y in the general formula (III) include halogen, hydroxy, oxo, lower alkyl, lower alkoxy, hydroxy-lower alkyl, lower alkoxy-lower alkyl, aryl, aryl-lower alkyl, carboxy, lower alkylcarbonyl, lower alkoxycarbonyloxy, lower alkoxycarbonyl, carbamoyl, mono-or di-lower alkyl-amino-lower alkyl, and -CO-NH-Alk-R1n Here, two substituents in combination may be bridged as lower alkylene, and two substituents may be substituted on the same carbon atom.

The symbols in the formula have the following meanings:

-Alk-: lower alkylene, Rln: hydroxy or a saturated heterocyclic group).
Examples of the substituent of the "lower alkyl which may be substituted" of Rle in Z of the general formula (IV) include lower cycloalkyl, lower alkoxy, carboxy, carbamoyl, a saturated heterocyclic group, aryl, and heteroaryl, wherein the aryl may have a substituent selected from the group consisting of lower alkyl, lower alkoxy, and carboxy groups, Examples of the substituent of the "lower alkyl which may be substituted" of Rlf in Z of the general formula (IV) include hydroxy, lower alkoxy, mono- or di-lower alkyl amino, aryl which may be substituted with halogen, and heteroaryl.

Examples of the substituent of the "aryl which may be substituted" and the "heteroaryl which may be substituted"
of R1f in Z of the general formula (IV) include halogen, lower alkyl, lower alkoxy, and aryl.

Examples of the substituent of the "aryl which may be substituted" of Rlh in Z of the general formula (IV) include halogen and aryl.

The compound of the present invention represented by the general formula (I) may have asymmetric carbons depending on the kind of the substituents, and thus optical isomers may be present. The present invention includes the isolated counterparts of either of a mixture of these optical isomers, and an isolated form thereof. The compound of the present invention may have tautomers, and the present invention also encompasses isolated isomers or a mixture thereof. Examples of these tautomers include a tautomer of 2-hydroxypyridine and 2-pyridone. Also, the labeled compounds, that is, the compounds having at least one element in the compounds of the present invention substituted with radioactive isotopes or non-radioactive isotopes are also included in the present invention.
Furthermore, the "pharmaceutically acceptable prodrugs" of the compounds represented by the general formula (I) are also included in the present invention.
The "pharmaceutically acceptable prodrug" is a compound having a group which is converted into a group such as CO2H, NH2, and OH by solvolysis or under a physiological condition to produce the compound (I) of the present invention. Examples of the group capable of forming a prodrug include those as described in "Prog. Med., 5, 2157-2161 (1985), and "Iyakuhin no Kaihatsu (Development of Drugs) (Hirokawa Shoten, 1990), vol. 7, Bunshi Sekkei (Molecular Design)", 163-198.

The salt of compounds (I) of the present invention are the pharmaceutically acceptable salts, and specific examples thereof include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, aspartic acid, and glutamic acid.
Depending on the kind of substituents, the compounds may form a salt with a base, and examples thereof include salts with inorganic bases such as sodium, potassium, magnesium, calcium, aluminum, and lithium, and with organic bases such as methylamine, ethylamine, ethanolamine, lysine, and ornithine, and ammonium salts.

In addition, the compound (I) of the present invention and a salt thereof also include various hydrates and solvates, and polymorphic substances thereof.
(Preparation Methods) The compound according to the present invention and a pharmaceutically acceptable salt thereof can be prepared by applying various known synthetic methods, utilizing characteristics based on their basic skeltons or the type of the substituents. Representive preparation methods are exemplified hereinafter. Further, depending on the type of the functional groups, it is in some cases effective from the viewpoint of the preparation techniques to protect the functional group with an appropriate protecting group, or to replace it by a group which may be easily converted into the functional group, during the steps of from starting materials to intermediates. Thereafter, if desired, the protecting group may be removed to obtain a desired compound. Examples of such a functional group include a hydroxyl group, a carboxyl group, and an amino group, and examples of a protecting group thereof include those as described in "Protective Groups in Organic Synthesis", edited by T.W. Greene and P.G.M. Wuts, (USA), 3rd edition, 1999, which may be optionally selected and used in response to the reaction conditions. In such a method, the desired compound can be obtained by introducing the protecting group to carry out the reaction, and then, if desired, removing the protecting group or converting it into a desired group.

In addition, a prodrug of the compound (I) or a salt thereof can be prepared by introducing a specific group during the stage of from starting materials to intermediates, similar to the aforementioned protecting groups, or by carrying out the reaction using the obtained compound (I). The reaction can be carried out by employing a method conventionally known to. a person skilled in the art, such as common esterification, amidation, and acylation.

(First Preparation Method) [Chem. 22]

O
A A N
NH2 HO2C N N I~R' R' Step 1 H
+ ~

Q Rz X Q

(1) (2) (I) (wherein X, A, Q, R1, and R2 have the same meanings as defined above, respectively. The same shall be applied hereinafter.) (Step 1) This step is a process for preparing a compound (I) by subjecting a compound (2) or a reactive derivative thereof, and a compound (1) or a salt thereof to amidation by a conventional method, and then if desired, removing the protecting group.

Examples of the reactive derivative of the compound (2) include a common ester such as methyl ester, ethyl ester, and tert-butyl ester; an acid halide such as acid chloride and acid bromide; an acid azide; an active ester with 1-hydroxybenzotriazole, p-nitrophenol, N-hydroxysuccinimide, or the like; a symmetric acid anhydride; a mixed acid anhydride of a halocarboxylic acid alky ester such as an alkyl halocarbonate, a pivaloyl halide, a p-toluenesulfonyl chloride, and the like; and a mixed acid anhydride such as a phosphoric mixed acid anhydride obtained by the reaction of diphenylphosphoryl chloride with N-methylmorpholine.

If the compound (2) is reacted as a free acid, or is reacted without isolation of an active ester, or the like, amidation that can be usually used by a person skilled in the art can be used, but a method in which a condensing agent such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC-HC1), or dicyclohexylcarbodiimide (DCC), carbonyldiimidazole (CDI), diphenylphosphoryl azide (DPPA), diethylphosphorylcyanide (DEPC), 0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) are allowed to undergo the reaction in the presence of 1-hydroxybenzotriazole (HOBt), a method in which phosphorus oxychloride is allowed to undergo the reaction in a pyridine solvent, or a condensing agent-carrying polystyrene resin such as a PS-carbodiimide (Argonaut Technologies, Inc., USA) or a PL-DCC resin (Polymer Laboratories, UK) are appropriately used.

Also, in some cases, it is preferable to use an isocyanate-carrying polystyrene resin, such as PS-Isocyanate (Argonaut Technologies, Inc., USA), in order to remove an excessive amount of amine after completion of the reaction. In addition, it is preferable in some cases to use a quaternary ammonium salt-carrying polystyrene resin, such as MP-Carbonate (Argonaut Technologies, Inc., USA), in order to remove an excessive amount of carboxylic acid, and the aforementioned additive such as HOBt after completion of the reaction.

Particularly, in the present invention, an acid chloride method, and a method for performing a reaction in the coexistence of an active esterifying agent and a condensing agent are convenient.

The reaction varies depending on the reactive derivatives, condensing agents, or the like to be used, but usually, this is carried out under cooling, from under cooling to at room temperature, or from at room temperature to under heating, in a solvent inert to the reaction, such as halogenated hydrocarbons such as dichlorometahane, dichloroethane and chloroform; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as ether and tetrahydrofuran (THF); esters such as ethyl acetate (EtOAc); acetronitrile, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), and dimethyl sulfoxide (DMSO).

Furthermore, in the reaction, it is in some cases advantageous in advancing the reaction smoothly to carry out the reaction with an excess amount of the compound (1) or in the presence of a base such as N-methylmorpholine, trimethylamine, triethylamine, diisopropylethylamine, N,N-dimethylaniline, pyridine, 4-(N,N-dimethylamino)pyridine, picoline, and lutidine. Also, a salt formed from a weak base and a strong acid, such as pyridine hydrochloride, pyridine p-toluenesulfonate, an.d N,N-dimethylaniline hydrochloride, may be used. Pyridine may be used as a solvent.

Particularly, it is preferable to carry out the reaction in the presence of a base such as triethylamine in a solvent such as THF and DMF.

(Second Preparation Method) [Chem. 23]

O
la A N N Rla L ~
l ~ H N~ /Rlb -N~Rlb Rz s (4) Q
(I a) Step 2 O
O Step 2 A N
\N Y~ N ~ZH S
N N t-~
H Rz g L~ N Y~ Q

Q
(5) (I b) (3) Step 2 H-O-RA O
A N A
N I ~~O
H Rz S
Q
(I c) (wherein Z1 represents halogen, SMe, SOMe, SOZMe, SO3H, or OTf. L1 represents hydrogen or methyl. RA can be any one of the substituents that are usually used, preferably lower alkyl, and more preferably lower alkoxy-lower alkyl. Y1, Rla, and Rlb have the same meanings as defined above, respectively. The same shall be applied hereinafter) The nucleophilic substitution reaction of this step can be carried out in a solvent inert to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, esters, alcohols such as methanol, ethanol, and isopropanol, acetonitrile, DMF, DMA, and DMSO, in the presence of an organic base such as triethylamine and diisopropylethylamine, and/or an inorganic base such as potassium carbonate, sodium carbonate, cesium carbonate, sodium hydrogen carbonate, and sodium hydride, by allowing the compound (4), (5), or HO-RlA to undergo the reaction with the compound (3). Further, in order to accelerate the reaction, a catalyst such as dimethylaminopyridine may be added. Also, instead of the organic base and/or the inorganic base, the compound (4) or (5) may be used in an excessive amount. The reaction varies depending on the base to be used, but it can be carried out from under cooling to at room temperature, from at room temperature to under heating, or from at room temperature to under reflux.
Also, in some cases, it is preferable to use an isocyanate-carrying polystyrene resin, such as PS-Isocyanate (Argonaut Technologies, Inc., USA), in order to remove an excessive amount of amine after completion of the reaction.

(Third Preparation Method) [Chem. 24]

O (7) O

N R' R-N \>--R
H Rz X \-TMS R

Step 3 R7 (6) R9 (I d) (wherein Ll represents lower alkyl. R7 and R9 have the same meanings as defined above, respectively. The same shall be applied hereinafter.) The 1,3-dipolar cycloaddition reaction of this step is a step for carrying out cycloaddition by azomethine ylide generated in the reaction system for the compound (6). For various alkoxymethylsilyl methylamine, the reaction can be carried out by allowing the compound (6) to undergo the reaction in the presence of an organic acid such as trifluoroacetic acid, or a Lewis acid such as trimethylsilyl trifluoromethane sulfonate, cesium fluoride, lithium fluoride, tetrabutylammonium fluoride, and zinc chloride, in an organic solvent inert to the reaction, such as halogenated hydrocarbons, aromatic hydrocarbons, ethers, esters, acetonitrile, DMF, DMA, and DMSO. The reaction varies depending on the acid or the solvent to be used, but it can be carried out from under cooling to at room temperature, from at room temperature to under heating, or from at room temperature to under reflux.

(Fourth Preparation Method) Furthermore, the compound of the present invention having various functional groups represented in the formula (I) can be prepared from the compound of the present invention obtained by First Preparation Method, Second Preparation Method, or Third Preparation Method, by any combination of well-known processes that can be usually employed by a person skilled in the art, such as alkylation, acylation, substitution reaction, oxidation, reduction, and hydrolysis. This step is not limited to a one-step reaction, but it may be consisted of a multi-step reaction. Further, the processes that can be usually employed by a person skilled in the art are not limited to the application for the compound of the present invention, but they may be used in the application for the preparation intermediates.

Representative reactions are exemplified hereinafter.
(1) Amidation A compound having an amide group among the compounds (I) of the present invention can be prepared by reacting a compound having an amino group as a starting material with a carboxylic acid and a reactive derivative thereof, or by reacting a compound having carboxylic acid as a starting material with an amine. The reaction can be carried out in accordance with Step A of First Preparation Method, for example, with reference to a method as described in "Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)", vol. 22 (1992) (Maruzen), or "Compendium of Organic Synthetic Methods", vols. 1 to 3, or the like.

(2) Sulfonylation A compound having a sulfonamide group among the compounds (I) of the present invention can be prepared by reacting a compound having an amino group as a starting material with a reactive derivative of sulfonic acid. The reaction can be carried out, for example, with reference to a method as described in "Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)", edited by The Chemical Society of Japan, vol. 24 (1992) (Maruzen).

(3) Synthesis of Carbamate A compound having a carbamate group among the compounds (I) of the present invention can be prepared by reacting a compound having an amino group as a starting material with a carbonate derivative. The reaction can be carried out, for example, with reference to a method as described in "Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)", edited by The Chemical Society of Japan, vol. 20 (1992) (Maruzen).

(4) Synthesis of Urea and thiourea A compound having an urea group among the compounds (I) of the present invention can be prepared by reacting a compound having an amino group as a starting material with an isocyanate compound, an aminocarbonyl halide, or the like.

A compound having a thiourea group among the compounds (I) of the present invention can be prepared by reacting a compound having an amino group as a starting material with a thioisocyanate compound, etc.

The reaction can be carried out, for example, with reference to a method as described in "Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)", edited by The Chemical Society of Japan, vol. 20 (1992) (Maruzen).
(5) 0-acylation A compound having an ester group among the compounds (I) of the present invention can be prepared by reacting a compound having an alcohol group as a starting material with a carboxylic acid derivative. The reaction can be carried out, for example, with reference to a method as described in "Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)", edited by The Chemical Society of Japan, vol. 22 (1992) (Maruzen).

(6) N-alkylation A compound having a secondary amine or a tertiary amine among the compounds (I) of the present invention can have an alkyl group introduced thereinto by reacting a compound having a primary amino group or a secondary amino group as a starting material with another alkylating agent or an epoxy derivative. As the alkylating agent, alkyl halide, an organic sulfonic ester of alcohol, and the like are preferred.

The reaction is carried out by mixing the materials from under cooling to under heating in a solvent inert to the reaction, such as aromatic hydrocarbons, halogenated hydrocarbons, ethers, ketones such as acetone and 2-butanone, acetonitrile, ethyl acetate, DMF, DMA, and NMP.
It is sometimes advantageous in smoothly advancing the reaction to carry out the reaction in the presence of an organic base or an inorganic base.

(7) Reductive alkylation A compound having a secondary amine or a tertiary amine among the compounds (I) of the present invention can have an alkyl group introduced thereinto by reacting a compound having a primary amino group or a secondary amino group as a starting material with an aldehyde and a ketone for performing reductive alkylation, in the presence of an reducing agent such as sodium borohydride and sodium triacetoxy borohydride, or under a catalytic reduction condition by palladium-carbon under a hydrogen atmosphere.
This can exemplified by a method as described in "Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)", edited by The Chemical Society of Japan, vol. 20 (1992) (Maruzen), or the like. It is sometimes preferable to use a reducing agent-carrying polystyrene resin, such as MP-Triacetoxyborohydride (Argonaut Technologies, Inc., USA) as a reducing agent.

(8) oxidation A compound having a sulfonyl group or a sulfenyl group among the compounds (I) of the present invention can be prepared by subjecting a compound having a sulfide group to an oxidation reaction. The compound having an adjacent diol can be prepared by subjecting a corresponding olefin product to an Os oxidation, etc. The reaction can be carried out, for example, with reference to a method as described in "Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)", edited by The Chemical Society of Japan, vol. 23 (1992) (Maruzen).

(9) Reduction reaction A compound having a primary alcohol group among the compounds (I) of the present invention can be prepared by subjecting a corresponding compound having a carboxyl group to a reduction reaction. The reaction can be carried out, for example, with reference to a method as described in "Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)", edited by The Chemical Society of Japan, vol. 26 (1992) (Maruzen).

(10) Catalytic reduction reaction In the synthesis of the compound of the present invention, a corresponding reduced product can be prepared by subjecting a compound having double bonds, and a compound having a halogen group as starting materials to catalytic reduction reaction. The reaction can be carried out, for example, with reference to a method as described in "Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)", edited by The Chemical Society of Japan, vol. 26 (1992) (Maruzen).
(11) ipso substitution reaction A compound having an alkoxypyridine or aminopyridine skelton among the compounds (I) of the present invention can be prepared by reacting a corresponding compound having a chloropyridyl group as a starting material with an alkoxides, an amine, or the like. The reaction can be carried out, for example, with reference to Step A of Second Preparation Method. Further, under the same condition, an azide group can be once introduced by sodium azide, and then a catalytic reduction, or the like can be carried out to convert the group to a primary amino group.
(12) Palladium coupling reaction A compound having a cyanoaryl group among the compounds (I) of the present invention can be prepared by cross-coupling a corresponding compound having a halogenated aryl group as a starting material with zinc cyanide, or the like in the presence of a palladium catalyst. Further, a compound having an alkenylaryl group or an alkylaryl group can be prepared by cross-coupling a corresponding compound having a halogenated aryl group as a starting material with an organic tin reagent, boric acid, or the like in the presence of a palladium catalyst. The reaction can be carried out, for example, with reference to a method as described in "Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)", edited by The Chemical Society of Japan, vol. 25 (1992) (Maruzen).
(13) Addition reaction via lithiation A compound having a carboxylphenyl group among the compounds (I) of the present invention can be prepared by subjecting a compound having a bromophenyl group as a starting material to a lithium-halogen exchange reaction by allowing alkyl lithium to undergo the reaction, and then reacting the resultant with carbon dioxide. The reaction can be carried out, for example, with reference to a method as described in "Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)", edited by The Chemical Society of Japan, vol. 20 (1992) (Maruzen).
(14) Hydrolysis reaction A compound having a carboxyl group or an amide group among the compounds (I) of the present invention can be prepared by subjecting a corresponding compound having an ester group, an amide group, or a cyano group to hydrolysis. The reaction can be carried out, for example, with reference to a method as described in "Protective Groups in Organic Synthesis (3rd edition)" as described above, or "Jikken Kagaku Koza (Courses in Experimental Chemistry) ( 4th edition) ", edited by The Chemical Society of Japan, vol. 22 (1992) (Maruzen).
(15) Dehydration reaction A compound having a cyano group among the compounds (I) of the present invention can be prepared by subjecting a compound having a carboxamide group to a dehydration reaction. The reaction can be carried out, for example, with reference to a method as described in "Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)", edited by The Chemical Society of Japan, vol. 20 (1992) (Maruzen).

In various reactions as described above, it is in some cases preferable to use a primary amine-carrying polystyrene resin, such as PS-Trisamine (Argonaut Technologies, Inc., USA), or the like, in order to remove an electrophilic reagent (acid chloride, sulfonyl chloride, isocyanate, or the like), or to use a strong cationic exchanger, such as BondElut SCX (Varian Ltd., USA) to purify basic substances, or the like.

The starting materials used in the preparation of the compounds of the present invention can be prepared, for example, by using the methods described in Reference Examples as described below, well-known methods, or methods apparent to a person skilled in the art, or variations thereof.

(Starting Material Synthesis 1) [Chem. 251 i 2 N02 NH2 N Step A1 Step B1 l N -3- N
A NO2 + R7 Q R$ Q~ Ql Z2 R9 R7 9 R$ R7 9 R$
R R
(8) (9) (1 0) (1 a) (wherein Z2 represents halogen or -0-S02CF3. L2 represents hydrogen or methyl. The ring of Q1 has a nitrogen atom as a ring-forming atom, and represents an alicyclic heterocycle that bonds with the ring of A at the nitrogen atom. R7, R8, and R9 have the same meanings as defined above, respectively. The same shall be applied hereinafter.) <Step A1>

This step is a process for preparing a compound (10) by carrying out a substitution reaction at an ortho position of the nitro group of the compound (8) . The substitution reaction of this step can be carried out in the same manner as in Step 2 of Second Preparation Method.

<Step B1>

This step is a process for preparing a compound (la) by subjecting the nitro compound (10) to reduction. The reduction reaction of this step can be carried out by using a reduction reaction for a nitro group, which can be usually employed by a person skilled in the art. For example, it can be exemplified by a reduction reaction using an reducing agent such as reduced iron and tin chloride, and a hydrogenation reaction using palladium-carbon, rhodium-carbon, or the like as a catalyst. The reaction can be carried out, for example, with reference to a method as described in "Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)", edited by The Chemical Society of Japan, vol. 26 (1992) (Maruzen).

(Starting Material Synthesis 2) [Chem. 26]

a A
Z A Np A NHZ NH2 z A + Qz NQZ ~ N~Rs Step A2 Q2 Step BZ (~z Step C2 ~
R
Z3 R9 R, N R$ R~ N R8 R' N R8 (1 1) (1 2) (13) (14) (1 b) (wherein Z3 represents halogen or -O-S02CF3r and Z4 represents -B(OH)2, dialkylboron, dialkoxyboron, or trialkyltin. Alternatively, Z3 may represent -B(OH)2, dialkyl boron, dialkoxyboron, or trialkyltin, and Z4 may represent halogen or -O-SO2CF3. The rings of Q2 and Q3 represent aliphatic nitrogen-containing heterocycles that bond with the ring of A at the carbon atom, respectively.
The same shall be applied hereinafter.) <Step A2>

This step is a reaction of two cyclic skeltons comprising a combination of the compound (11) and the compound (12), preferably in the presence of a transition metal catalyst and a suitable additive to form a carbon-carbon bond. Representative methods thereof include a method as described in "Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)", edited by The Chemical Society of Japan, vol. 25 (1992) (Maruzen). As the transition metal catalyst, various palladium complexes such as tetrakis(triphenylphosphine)palladium, and various nickel complexes such as dibromobis(triphenylphosphine)nickel can be preferably used. As the additive, various ligands such as triphenylphosphine, sodium carbonate, and zinc can be preferably used, but it is preferable to suitably select an additive depending on the employed methods. Usually, this reaction is carried out in a solvent from at room temperature to under heating.

<Step B2>

This step is a process for preparing a compound (14) by subjecting the nitro compound (13) to reduction. The reduction of the nitro group in this step can be carried out in the same manner as in Step B1 of Starting Material Synthesis 1, but particularly preferred is a reduction reaction using a reducing agent such as reduced iron and tin chloride.

<Step C2>

This step is a process for preparing a compound (lb) by subjecting the double bonds of the compound (14) to reduction. For the reduction reaction of this step, a reduction reaction that can be usually employed by a person skilled in the art can be used. For example, the reaction can be exemplified by a catalytic reduction reaction using palladium-carbon, or the like as a catalyst under a hydrogen atmosphere.

(Starting Material Synthesis 3) [Chem. 27]

A A NH
Step A3 A H-L3 NH2 NH2 A 2 CA( ~ HO Ste 30 HO Step ~ ~ Step Q3 H R7 N R8 R7 I R$ R~ Ra R7 Ra 1 g R9 R9 R9 R

(1 5) (1 6) (1 7) (1 8) (1 b) (wherein Z5 represents halogen or hydrogen, and L3 represents a protecting group for amine. Q2 and Q3 have the same meanings as defined above, respectively. The same shall be applied hereinafter.) <Step A3>

This step is a process for preparing a compound (16) by allowing alkyl lithium to undergo the reaction with the compound (15) for a lithium-halogen exchange or deprotonation reaction to produce aryl lithium, and then subjecting the ketone to an addition reaction. A method as described in "Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)", edited by The Chemical Society of Japan, vol. 25 (1992) (Maruzen), and an equivalent method.

<Step B3>

This step is a process for preparing a compound (17) by subjecting a substituent L3 on nitrogen of the compound (16) to deprotection. For the reaction, a deprotection condition by a conventional method corresponding to the substituent L3 can be used, and for example, a method as described in the deprotection reaction of an amino group in "Protective Groups in Organic Synthesis (3rd edition)", or the like can be applied.

<Step C3>

This step is a method for preparing an olefinic product by subjecting a hydroxy group of the compound (17) to a hydroxy group-elimination reaction. The reaction can be carried out under a basic condition via halogenation and sulfonation in addition to an acid catalyst dehydration reaction. A method as described in "Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)", edited by The Chemical Society of Japan, vol. 19 (1992) (Maruzen) or an equivalent method can be employed.

<Step D3>

This step is a process for preparing a compound (lb) by subjecting the double bonds of the compound (18) to reduction. The reduction reaction of this step can be carried out in the same manner as in Step C2 of Starting Material Synthesis 2.

Furthermore, these Steps B3 to D3 can be carried out in varying order depending on the need. For example, a method in which from the compound (16), a dehydration reaction is carried out in Step C3r deprotection of the substituent L3 on nitrogen is carried out in Step B3, and then reduction of the double bonds carried out in Step D3, or other methods can be exemplified.

(Starting Material Synthesis 4) [Chem. 281 H N Step A4 L4 O2o N Step B HO2C N
2 ~R~ D's ~R, ~ ~ ~R, g RR2 S
(19) (20) (2a) (wherein L4 represents a protecting group for carboxylic acid. The same shall be applied hereinafter.) <Step A4>

This step is a method for constructing a thiazole ring by allowing an a-haloketone, representatively such as bromopyruvic ester, to undergo the reaction with a thioamide or thiourea. Those methods as described "Comprehensive Organic Chemistry", vol. 4, or an equivalent method can be employed. In addition, it is in some cases preferable to add trifluoroacetic anhydride in order to promote a cyclization reaction.

<Step B4>

This step is a process for preparing a carboxylic acid derivative (2a) by subjecting a carboxylic acid ester derivative (20) to hydrolysis. For this reaction, a hydrolysis condition by a conventional method can be used, and for example, a method as described in the deprotection reaction of a carboxyl group in "Protective Groups in Organic Synthesis (3rd edition)" as described above, or the like can be applied.

(Starting Material Synthesis 5) [Chem. 29]

H2N Step A5 HO2C N
S R1 -~~ ~ \Rl (2 1 ) (2 a) <Step A5>

This step is a method for constructing a thiazole ring by allowing an a-haloketone, representatively such as bromopyruvic acid, to undergo the reaction with a thioamide or thiourea. The reaction can be carried out in the same manner as in Step A4 of Starting Material Synthesis 4.

(Starting Material Synthesis 6) [Chem. 30]

L4 02C N Step L4 02C PJ Step B6 HO 2C N
~ \Z' ~ ~ ~S~R' ~ 2~ ~R' R z S R2 R S
(22) (23) (2 a) <Step A6>

This step is a process for preparing a compound (23) by carrying out a substitution reaction of the compound (22) at a 2 position of the thiazole. The substitution reaction of this step can be carried out in the same manner as in Step 2 of Second Preparation Method.

<Step B6>

This step is a process for preparing a compound (2a) by subjecting the carboxylic acid ester derivative (23) to hydrolysis. The hydrolysis reaction of this step can be carried out in the same manner as in Step B4 of Starting Material Synthesis 4.

(Starting Material Synthesis 7) [Chem. 31]

H N Step A7 L4 02C N Step HO2C N
2p R1 ~ ~~ R1 ~ ~}-Rl 30 R z R 2 O

(24) (25) (2 b) <Step A7>

This step is a method for constructing an oxazole ring by allowing an a-haloketone, representatively such as bromopyruvic acid ester, to undergo the reaction with an amide or urea. A method as described in "Heterocyclic Compounds" edited by Turchi, vol. 45, or "Heterocyclic Compounds" edited by Palmer, vol. 60, Part A, or an equivalent method can be employed.

<Step B7>

This step is a process for preparing a compound (2b) by subjecting the carboxylic acid ester derivative (25) to hydrolysis. The hydrolysis reaction of this step can be carried out in the same manner as in Step B4 of Starting Material Synthesis 4.

(Starting Material Synthesis 8) [Chem. 32]

HO Rl (2 7) HO~NH2 L4OZC N 1 L4 02C N 1 0 Hp~O R Step \R 310 Step A8 Bs 0 (26) (28) (29) 11 \>R, -~ 11 \>-R
Step Cg 0 Step D8 0 (30) (2 c) <Step A8>

This step is a process for carrying out an amidation reaction from the compound (26) and the compound (27). The reaction can be carried out in accordance with Step 1 in First Preparation Method, for example, with reference to a method as described in "Jikken Kagaku Koza (Courses in Experimental Chemistry) (4th edition)", edited by The Chemical Society of Japan, vol. 22 (1992) (Maruzen), or "Compendium of Organic Synthetic Methods" as described above, vols. 1 to 3, or the like.

<Step B$>

This step is a method for constructing an oxazoline ring by carrying out a dehydration-cyclization reaction from the compound (28) The cyclization of this step can be carried out, for example, with reference to a method as described in Phillips, A. J.; Wipf, P.; Williams, D. R.; et al., Org Lett, 2000, 2(8), 1165-1168, "Heterocyclic Compounds" as described above, vol. 60, Part A, Part B, etc.

<Step C8>

This step is a method for constructing an oxazole ring by carrying out an oxidation reaction from the compound (29) . The cyclization of this step can be carried out, for example, with reference to a method as described in Phillips, A. J.; Wipf, P.; Williams, D. R.; et al., Org Lett, 2000, 2(8), 1165-1168, or "Heterocyclic Compounds" as described above, vol. 60, Part A, or the like.

<Step D8>

This step is a process for preparing a compound (2c) by subjecting the carboxylic acid ester derivative (30) to hydrolysis. The hydrolysis reaction of this step can be carried out in the same manner as in Step B4 of Starting Material Synthesis 4.

(Starting Material Synthesis 9) [Chem. 33]

(32) L4 ~2C N 2 Z3 Z4 Ar L40 C ~ N Ar HO2C ( N}-Ar I 30 2/ \ ~ O

Step A9 R Step B~

(31) (33) (2d) (wherein Ar represents aryl which may be substituted, or heteroaryl which may be substituted, and bonds with an oxazole ring at the carbon atoms on the ring. Z3 and Z4 have the same meanings as defined above, respectively. The same shall be applied hereinafter.) <Step A9>

This step is a method for synthesizing a biaryl compound from the compound (31) and the compound (32). The reaction of this step can be carried out, for example, in accordance with HODGETTS, K. J.; KERSHAW, M. T.; Org Lett, 2002, 4(17), 2905-2907.

<Step B9>

This step is a process for preparing a compound (2d) by subjecting the carboxylic acid ester derivative (33) to hydrolysis. The hydrolysis reaction of this step can be carried out in the same manner as in Step B4 of Starting Material Synthesis 4.

Furthermore, in Starting Material Syntheses 1 to 9, the substituents to bond with the compound (I) of the present invention can be converted in a suitable period of time in the above-described step for proceeding in the next step. Examples of the method for the aforesaid conversion include a method in which of Starting Material Synthesis 3, a Boc group is introduced to the position of R9, and an alkylation reaction is carried out at a suitable periods of time, before Step B3, before Step C3, or before Step D3, and after deprotection of the Boc group, to conversion into a partial structure R9 of the compound according to the present invention.

The reaction products obtained by each of Preparation Methods can be isolated and purified as their free compounds, and salts or various solvates thereof, such as hydrates. The salts can be prepared after carrying out a conventional salt formation treatment.

The isolation and purification can be carried out by employing common chemical operations such as extraction, concentration, removal by distillation, crystallization, filtration, recrystallization, and various chromatography.

Various isomers can be isolated in the standard method making use of the differences in physicochemical properties among isomers. For example, optical isomers can be separated by general optical resolution, for example, by fractional crystallization, chromatography, or the like.
In addition, the optical isomers can also be prepared from appropriate optically active starting material compounds.

The effects of the compounds of the present invention were confirmed by the following pharmacological tests.

1. Experiment to measure a receptor inhibitory activity using cells expressing a nerve growth factor receptor The nerve growth factor receptor inhibitory activity was measured by using the increase in a ligand-dependent calcium concentration in cells as an index. HEK293 cells (American Type Culture Collection) that stably expressed Human nerve growth factor receptor were dispensed onto a 96-well poly-D-lysine-coated plate (Product Name: Biocoat, PDL96W black/clear, by Nippon Becton Dickinson) to a 2x104 cells/well at the day before the experiment, and incubated overnight at 37 C under 5% carbon dioxide (C02) in a culture medium containing 10o fetal bovine serum (FBS) (Product Name: DMEM, Invitrogen Corporation). The culture medium was replaced by a washing solution: a Hank's balanced salt solution)(HBSS), containing a 1.5 M loading buffer (fluorescent indicator (Product Name: Fluo4-AM, Tong Ren Tang Technologies Co. Ltd.)), 20 mM 2-[4-(2-hydroxyethyl)-l-piperazinyl]ethanesulfonic acid (HEPES)-sodium hydroxide (NaOH), 2.5 mM Probenecid, 0.1% bovine serum albumin (BSA), and left to stand at room temperature for 3 hours, and the cells were washed using a plate washer (Product Name: ELx405, BIO-TEK instrument Corporation)in which a washing solution had been set up. The compound that had been preliminarily dissolved and diluted in a washing solution was added thereto, and set up in a system for measuring a calcium (Ca) concentration in a cell (Product Name: FLIPR, Molecular Devices Corporation).
After 5 minutes, a nerve growth factor (NGF, mouse derived 2.5S, Alomone) corresponding on 80% stimulation of a maximum response was added (to a final concentration of about 100 to 150 ng/ml) to measure the change in Ca concentrations in cells. A difference between a maximum value and a minimum value in Ca concentrations in cells was determined, and kept as measurement data. With a response upon addition of NGF being set at 0%, and a response upon addition of a buffer being set at 100%, the concentration causing 50% inhibition was determined as an IC50 value. The results are shown in the following Table 1. In the table, Ex represents Compound No. of Examples as described later.
From the results of this test, it was confirmed that the compound of the present invention has a nerve growth factor receptor inhibitory activity.

[Table 1]
Ex IC50 (nM) 11 4.3 69 4.7 311 2.6 356 8.8 380 9.5 449 2.4 492 2.3 662 2.4 942 4.6 2. Evaluation of the inhibitory activity of the compound on enhanced vascular permeability caused by NGF in rat The in vivo trkA receptor inhibitory activity of the compound was examined. A Wistar female rat (SLC) were forced to be orally administered with the compound (0.5%
methylcellulose solution) 10 mg/3 ml/kg or a vehicle (0.5%

methylcellulose solution) 3 ml/kg. Under ether anesthesia performed at 60 min after administration, physiological saline or 1 ug/ml NGF (NGF, mouse derived 2.5S, Alomone) was intracutaneously administered to the back at 50 ul/site, and then immediately a 1% Evans blue solution (dissolved in physiological saline) was administered through caudal vein at 3 ml/kg. At a time point of 10 min after the administration, the skin on the back was taken, and shaken in formamide for 16 hours. After shaking, an absorption of Evans blue extracted with formamide was measured by an absorption meter (wavelength: 620 nm), and the concentration was determined by a calibration curve method. A value obtained by subtracting the concentration of Evans blue at a site administered with physiological saline from the concentration of Evans blue at a site administered with NGF has a function dependent on NGF, and an inhibitory rate of the compound group was determined with a group administered with vehicle being set at 100%.
The results are shown in the following Table 2. In this test, it was confirmed that the compound of the present invention has an excellent inhibitory activity on enhanced vascular permeability caused by NGF in rat.

[Table 21 Ex Inhibition rate (%) 3. Effects of the compound on the cyclophosphamide (CPA)-induced urinary frequency in rat CPA (150 mg/5 ml/kg) was intraperitoneally administered to a Wistar female rat (Charles river laboratories), and after two days, the experiment was carried out. It was forced to be orally administered with distilled water (30 ml/kg), and then placed in a metabolic cage, and the voided urine weight and the urination frequency were continuously measured for 1 hour. The compound (0.5% methylcellulose solution) 3 or 10 mg/5 ml/kg, or a vehicle (0.5% methylcellulose solution) 5 ml/kg was orally administered, and after 5 to 30 min, the urinary functions were measured after loading water in the same manner as described above. A total voided urine weight was divided by the total urination frequency to determine an effective bladder capacity. With the value before administration of the compound being set at 100%, a rate of change in the effective bladder capacity caused by administration of the compound was determined. The results are shown in the following Table 3.

In this test, at 2 days after CPA treatment, the effective bladder capacity was decreased (about 0.5 ml), indicating urinary frequency condition. On the other hand, the compound of the present invention improved the urinary frequency condition. For example, Example 492 increased the effective bladder capacity up to 177%.

[Table 3]
Duration of Change rate of Dose evaluation after Ex effective bladder (mg/kg) administration (min.) capacity ( o ) 4. Effects of the compound on acetic acid-induced painful behaviors in rat 1% Acetic acid (99% distilled water) was intraperitoneally administered to a Wistar male rat (Charles river laboratories), and the frequency of pain behavior (writhing) between 10 min and 20 min after administration was measured. The compound (10 mg/5 ml/kg) or a vehicle(0.5o methylcellulose solution) was orally administered 5 mins before the administration of 1% acetic acid. With the frequency of the group administered with the vehicle being set at 100%, the inhibition rate of the writhing behavior frequency by the compound administration was determined. The results are shown in the following Table 4. In this test, the compound of the present invention exhibited an excellent analgesic action.

[Table 4]
Inhibition rate Ex M

From the results as described above, it was demonstrated that the compound of the present invention has a potent in vitro and in vivo trkA receptor inhibitory activity, and has a urinary symptom-improving action and an analgesic action. Accordingly, it can be expected that the compound of the present invention is useful as a therapeutic or prophylactic drug for various lower urinary tract diseases accompanied by urinary symptoms, and various pain diseases.

A pharmaceutical composition containing the compound (I) of the present invention or a salt thereof is prepared by using a carrier, an excipient or other additives that are usually used in the preparation of drugs.
Administration may be made in any one form for either oral administration by tablets, pills, capsules, granules, powders, and liquids, or for parenteral administration by injections for intravenous injection, and intramuscular injection, suppositories, percutaneous preparations, transnasal preparations, inhalations or the like. The dose is appropriately decided in response to an individual case by taking the symptoms, age and sex of the subject and the like into consideration, but is usually from about 0.001 mg/kg to about 100 mg/kg per day per adult in the case of oral administration, and this is administered in one portion or dividing it into 2 to 4 portions. Also, in the case of intravenous administration according to the symptoms, this is administered usually within the range of from 0.0001 mg/kg to 10 mg/kg per day per adult, once a day or two or more times a day. In addition, in the case of inhalation, this is administered generally within the range of from 0.0001 mg/kg to 1 mg/kg per adult, once a day or two or more times a day.

Regarding the solid composition of the present invention for oral administration, tablets, powders, granules, or the like are used. In such a solid composition, one or more active substances are mixed with at least one inactive excipient(s) such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinyl pyrrolidone, and magnesium aluminometasilicate. In a conventional method, the composition may contain inactive additives such as lubricants such as magnesium stearate, disintegrators such as carboxymethylstarch sodium, and solubilization assisting agents. As occasion demands, tablets or pills may be coated with a sugar coating, or a gastric or enteric coating agent.

The liquid composition for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, and the like, and contains a generally used inert solvent such as purified water or ethanol. In addition to the inert solvent, this composition may contain auxiliary agents such as solubilization assisting agents, moistening agents, and suspending agents, sweeteners, correctives, aromatics and antiseptics.

Injections for parenteral administration include aseptic aqueous or non-aqueous solutions, suspensions and emulsions. As the aqueous solvent, for example, distilled water for injection and physiological saline are included.
Examples of the non-aqueous solvent include propylene glycol, polyethylene glycol, plant oils such as olive oil, alcohols such as ethanol, and Polysorbate 80 (Pharmacopeia). Such a composition may further contain tonicity agents, antiseptics, moistening agents, emulsifying agents, dispersing agents, stabilizing agents, and solubilization assisting agent. These are sterilized, for example, by filtration through bacteria retaining filter, blending of germicides or irradiation. In addition, these can also be used by producing sterile solid compositions, and dissolving or suspending it in sterile water or a sterile solvent for injection prior to their use.

Regarding transmucosal agents such as inhalers and transnasal agents, those in a solid, liquid or semi-solid state are used, and may be produced in accordance with conventionally known methods. For example, excipients such as lactose and starch, and also pH adjusting agents, antiseptics, surfactants, lubricants, stabilizers, thickeners, and the like may be optionally added thereto.
For their administration, an appropriate device for inhalation or insufflation can be used. For example, a compound may be administered alone or as a powder of prescribed mixture, or as a solution or suspension by combining it with a pharmaceutically acceptable carrier, using conventionally known devices or sprayer, such as metered-dose inhalers. The dry powder inhaler or the like may be for single or multiple administration use, and a dry powder or a powder-containing capsule can be used.
Alternatively, this may be in a form such as a high pressure aerosol spray which uses an appropriate propellant, for example, a suitable gas such as chlorofluoroalkane, hydrofluoroalkane, and carbon dioxide.

In the preparation of the suppositories, a low melting point wax such as a mixture of fatty acid glycerides, or cocoa butter is dissolved, and an active ingredient is added thereto, followed by uniformly dispersing under stirring. Thereafter, it was poured into an appropriate mold and cooled for solidification. The liquid preparation includes solutions, suspensions, oil retention enemas, and emulsions, such as a solution in water or propyleneglycol.

EXAMPLES
Hereinafter, the compounds of the present invention will be described in more detail with reference to Examples. Also, the preparation methods of the starting material compounds are shown in Reference Examples.
Further, the preparation methods of the compounds of the present invention are not limited to the preparation methods of the specific Examples as below, and any combination of the preparation methods or well-known preparation methods can be used for preparation.

The following abbreviations are used in Reference Examples and Examples.

Me: methyl, Et: ethyl, Ac: acetyl, Ms: mesyl, Ph:
phenyl, Boc: tert-butoxycarbonyl, TBS: tert-butyldimethylsilyl, Tf: trifluoromethanesulfonyl, HOBt: 1-hydroxybenzotriazole, WSC-HCl: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, DCC:
dicyclohexylcarbodiimide, CDI: carbonyldiimidazole, DPPA:
diphenylphosphorylazide, DEPC: diethylphosphorylcyanide, THF: tetrahydrofuran, EtOAc: ethyl acetate, DMF: N,N-dimethylformamide, DMA: N,N-dimethylacetamide, DMSO:

dimethylsulfoxide.
Reference Example 1 2,4-Difluoro-6-nitrophenol was allowed to undergo the reaction with trifluoromethanesulfonic anhydride in pyridine to prepare 2,4-difluoro-6-nitrophenyl trifluoromethane sulfonic acid ester.
Reference Example 8 4-Chloro-3-nitrophenyl methylsulfide was allowed to undergo the reaction with m-chloroperbezoic acid in chloroform for performing oxidation of sulfide to prepare 4-chloro-3-nitrophenyl methylsulfoxide.
Reference Example 9 1,2,3-Trifluoro-4-nitrobenzene was allowed to undergo the reaction with potassium hydroxide and ethyl cyanoacetate in DMSO, and then with acetic acid and hydrochloric acid to prepare (2,3-difluoro-4-nitrophenyl)acetonitrile.
Reference Example 10 3-Chloro-2,6-difluorophenylacetonitrile was allowed to undergo the reaction with tetramethylammonium nitrate and trifluoromethanesulfonic anhydride in methylene chloride to prepare (3-chloro-2,6-difluoro-5-nitrophenyl)acetonitrile.

Reference Example 11 4-Chloro-3-nitrophenol was allowed to undergo the reaction with sodium chlorodifluoroacetate and cesium carbonate in DMF-water to prepare 1-chloro-4-(difluoromethoxy)-2-nitrobenzene.

Reference Examples 12 and 13 4-Chloro-5-nitropyridin-2(lH)-one was allowed to undergo the reaction with silver carbonate and methyl iodide in methylene chloride to prepare 4-chloro-2-methoxy-5-nitropyridine and 4-chloro-l-methyl-5-nitropyridin-2(1H)-one.

Reference Example 14 (2R,5S)-2,5-Dimethylpiperazine-l-carboxylic acid tert-butyl ester was allowed to undergo the reaction with potassium carbonate and bromoacetamide in DMF to prepare (2R,5S)-4-(2-amino-2-oxoethyl)-2,5-dimethylpiperazine-l-carboxylic acid tert-butyl ester.
Reference Example 15 4-Oxopiperidine-l-carboxylic acid tert-butyl ester was allowed to undergo the reaction with N-methylglycinamide and sodium triacetoxyborohydride in dichloroethane to prepare 4-[(2-amino-2-oxoethyl)(methyl)amino]piperidine-l-carboxylic acid tert-butyl ester.

Reference Example 19 4-Oxoazepane-l-carboxylic acid tert-butyl ester was allowed to undergo the reaction with sodium cyanide in an aqueous sodium hydrogen sulfite solution to prepare 4-cyano-4-hydroxyazepane-l-carboxylic acid tert-butyl ester.
Reference Example 20 4-Cyano-4-hydroxyazepane-l-carboxylic acid tert-butyl ester was allowed to undergo the reaction with 10% hydrogen chloride/methanol to prepare 4-hydroxyazepane-4-carboxylic acid methyl ester hydrochloride.

Reference Example 21 4-(2-Amino-2-oxoethyl)piperazine-l-carboxylic acid tert-butyl ester was allowed to undergo the reaction with 4 M hydrogen chloride/dioxane to prepare 2-piperazin-l-ylacetamide dihydrochloride.

Reference Example 27 2,4-Difluoronitrobenzene was allowed to undergo the reaction with 2-piperazin-1-ylacetamide and triethylamine in acetonitrile to prepare 2-[4-(5-fluoro-2-nitrophenyl)piperazin-1-yl]acetamide.

Reference Example 130 4-Oxoazepane-l-carboxylic acid tert-butyl ester was allowed to undergo the reaction with lithium diisopropylamide and 1,1,1-trifluoro-N-phenyl-N-[(trifluoromethyl)sulfonyl]methanesulfonamide in THF to prepare 4-{[(trifluoromethyl)sulfonyl]oxo}-2,3,6,7-tetrahydro-lH-azepine-l-carboxylic acid tert-butyl ester.
Reference Example 132 (4-Aminophenyl)acetonitrile was allowed to undergo the reaction with bis(pyridine)iodonium tetrafluoroborate in methylene chloride to prepare (4-amino-3-iodophenyl)acetonitrile.

Reference Example 135 2-Fluoro-6-nitrophenyl-trifluoromethane sulfonic acid ester was allowed to undergo the reaction with [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium (II), potassium phosphate, and 4-(4,4,5,5-tetramethyl-1,3,2-dioxabororan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester in DMF to prepare 4-(2-fluoro-6-nitrophenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester.

Reference Example 140 4-Amino-3-bromobenzonitrile was allowed to undergo the reaction with triethylamine, palladium acetate, 2-(dicyclohexylphosphino)biphenyl, and bis(pinacolato)diboron in dioxane, and then with 4-{[(trifluoromethyl)sulfonyl]oxo}-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester, barium hydroxide and water to prepare 4-(2-amino-5-cyanophenyl)-3,6-dihydropyridine-1(2H)-carboxylic acid tert-butyl ester.
Reference Example 171 1-(2-Nitrophenyl)-2,5-dihydro-lH-pyrrole was allowed to undergo the reaction with N-methylmorpholine-N-oxide, and a catalytic amount of osmium tetroxide in THF-water to prepare cis-1-(2-nitrophenyl)pyrrolidine-3,4-diol.
Reference Example 173 2-[4-(2-Bromo-4-fluoro-6-nitrophenyl)piperazin-l-yl]acetamide was allowed to undergo the reaction with zinc cyanide and tetrakistriphenylphosphinepalladium in DMF to prepare 2-[4-(2-cyano-4-fluoro-6-nitrophenyl)piperazin-l-yl]acetamide.

Reference Example 174 1-(5-Bromo-2-nitrophenyl)-4-hydroxypiperidine-4-carboxylic acid methyl ester was allowed to undergo the reaction with phosphorus oxychloride in pyridine to prepare 1-(5-bromo-2-nitrophenyl)-1,2,3,6-tetrahydropyridine-4-carboxylic acid methyl ester.

Reference Example 175 2-[4-(4-Formyl-2-nitrophenyl) piperazin-l-yl]acetamide was allowed to undergo the reaction with ethyl diethylphosphonoacetate and potassium carbonate in DMF to prepare ethyl (2E)-3-{4-[4-(2-amino-2-oxoethyl)piperazin-l-yl]-3-nitrophenyl}acrylate.

Reference Example 176 1-(3-Nitropyridine-2-yl)piperidine-4-carboxamide was allowed to undergo the reaction with palladium-carbon in a methanol-THF mixed solution, under a hydrogen atmosphere for performing reduction of a nitro group to prepare 1-(3-aminopyridine-2-yl)piperidine-4-carboxamide.
Reference Examples 276 and 277 2-[4-(6-Chloro-3-nitropyridine-2-yl)piperazin-l-yl]acetamide was allowed to undergo the reaction with potassium carbonate and ethyl cyanoacetate in DMF, and then with trifluoroacetic acid. This was allowed to undergo the reaction with 10% palladium-carbon and hydrogen in methanol to prepare 2-{4-[3-amino-6-(cyanomethyl)pyridin-2-yl]piperazin-1-yl}acetamide and 2-{5-amino-6-[4-(2-amino-2-oxoethyl)piperazin-1-yl]pyridin-2-yl}-N-tert-butylacetamide.

Reference Example 278 2-[4-(4-Bromo-2-nitrophenyl)piperazin-1-yl]acetamide was allowed to undergo the reaction with rhodium-carbon in a methanol-THF mixed solution under a hydrogen atmosphere for performing reduction of a nitro group to prepare 2-[4-(2-amino-4-bromophenyl)piperazin-1-yl]acetamide.
Reference Example 284 2-[4-(6-Amino-3-chloro-2-cyanophenyl)piperazin-l-yl]acetamide was allowed to undergo the reaction with palladium-carbon in methanol under a hydrogen atmosphere for performing dechlorination to prepare 2-[4-(2-amino-6-cyanophenyl)piperazin-1-yl]acetamide hydrochloride.

Reference Example 286 2-[4-(4-Chloro-2-nitrophenyl)piperazin-1-yl]acetamide was allowed to undergo the reaction with reduced iron in acetic acid for performing reduction of a nitro group to prepare 2-[4-(4-chloro-2-aminophenyl)piperazin-l-yl]acetamide.

Reference Example 303 1-(4-Nitro-l-oxidepyridin-3-yl)piperidine-4-carboxamide was allowed to undergo the reaction with reduced iron in acetic acid to prepare 1-(4-aminopyridin-3-yl)piperidine-4-carboxamide.

Reference Example 304 1-Benzyl-3-(2-nitrophenyl)pyrrolidine was allowed to undergo the reaction with palladium-carbon in methanol under a hydrogen atmosphere for performing reduction of a nitro group, and then ammonium formate was added thereto for performing debenzylation. This was allowed to undergo the reaction with di-tert-butyl dicarbonate to prepare 3-(2-aminophenyl)pyrrolidine-l-carboxylic acid tert-butyl ester.

Reference Example 305 1-(2-Aminophenyl)-3-pyrrolidinecarboxylic acid methyl ester was allowed to undergo the reaction with formamide and sodium methoxide in DMF under an argon atmosphere to prepare 1-(2-aminophenyl)-3-pyrrolidine carboxamide.
Reference Example 308 2-Bromopyridine-3-amine was allowed to undergo the reaction with trifluoroacetic anhydride in THF to prepare N-(2-bromopyridin-3-yl)-2,2,2-trifluoroacetamide.

Reference Example 309 Methyllithium and butyllithium were added to a solution of N-(2-Bromophenyl)-2,2,2-trifluoroacetamide in THF, followed by allowing to undergo the reaction with 4-oxo-l-piperidinecarboxylic acid tert-butyl ester to prepare 4-hydroxy-4-[2-[(trifluoroacetyl)amino]phenyl]-1-piperidinecarboxylic acid tert-butyl ester.

Reference Example 312 A THF-methanol solution of 4-hydroxy-4-{2-[(trifluoroacetyl)amino]phenyl}-1-piperidinecarboxylic acid tert-butyl ester was allowed to undergo the reaction with a 15% aqueous sodium hydroxide solution to prepare 4-(2-aminophenyl)-4-hydroxy-l-piperidinecarboxylic acid tert-butyl ester.

Reference Example 316 A solution of 4-(2-Aminophenyl)-4-hydroxy-l-piperidinecarboxylic acid tert-butyl ester in ethanol was allowed to undergo the reaction with a 4 M hydrogen chloride/dioxane solution to prepare 2-(1,2,3,6-tetrahydro-4-pyridinyl)aniline dihydrochloride.

Reference Example 318 A solution of N-(3-methoxyphenyl)-2,2-dimethylpropanamide in tetrahydrofuran was allowed to undergo the reaction with butyllithium, and then 4-oxo-1-piperidinecarboxylic acid tert-butyl ester was added thereto. The reaction solution was concentrated, and the residue was allowed to undergo the reaction with sulfuric acid to prepare 3-methoxy-2-(1,2,3,6-tetrahydropyridin-4-yl)aniline.

Reference Examples 322 and 323 4-(3-Aminopyridine-2-yl)piperidin-4-ol hydrochloride was allowed to undergo the reaction with 20% sulfuric acid.

This was allowed to undergo the reaction with potassium carbonate and 2-bromoacetamide in acetonitrile to obtain 2-(3-amino-3',6'-dihydro-2,4'-bipyridine-1'(2'H)-y1)acetamide and 2-[4-(3-aminopyridine-2-yl)-4-hydroxypiperidin-l-yl]acetamide.

Reference Example 324 A solution of 5-fluoro-2-(1,2,3,6-tetrahydro-4-pyridinyl)aniline dihydrochloride in pyridine was allowed to undergo the reaction with 4-morpholinecarbonylchloride to prepare 5-fluoro-2-[1-(4-morpholinylcarbonyl)-1,2,3,6-tetrahydro-4-pyridinyl]aniline.

Reference Example 325 A 4 M hydrogen chloride/EtOAc solution was added to a solution of 2-[4-(2-aminophenyl)-3,6-dihydro-1(2H)-pyridinyl]acetamide in ethanol, and followed by reacting with palladium-carbon under a hydrogen atmosphere for performing reduction of double bonds to prepare 2-[4-(2-aminophenyl)-1-piperidinyl]acetamide dihydrochloride.
Reference Example 333 3-Methyldihydrofuran-2(3H)-one was allowed to undergo the reaction with aqueous ammonia to prepare 4-hydroxy-2-methylbutanamide.

Reference Example 334 Triethylamine and 4-dimethylaminopyridine were added to a solution of 2-methylbutanamide in dichloromethane, and followed by reacting with benzoyl chloride to prepare 4-amino-3-methyl-4-oxobutylbenzoate.
Reference Example 335 A solution of [(lR)-2-hydroxy-l-methylethyl]carbamic acid tert-butyl ester in acetonitrile was allowed to undergo the reaction with methyl iodide in the presence of silver oxide (I) for alkylation to prepare [(1R)-2-methoxy-1-methylethyl)carbamic acid tert-butyl ester.

Reference Example 336 A solution of (S)-l-methoxy-2-propylamine in tetrahydrofuran was allowed to undergo the reaction with ethyl chloroformate in the presence of triethylamine to obtain [(1S)-2-methoxy-l-methylethyl]carbamic acid ethyl ester.

Reference Example 337 [(1R)-2-methoxy-l-methylethyl]carbamic acid tert-butyl ester was allowed to undergo the reaction with lithium aluminum hydride in tetrahydrofuran to obtain (2R)-1-methoxy-N-methylpropane-2-amine hydrochloride.

Reference Example 339 A 4 M hydrogen chloride/EtOAc solution was added to 2-methoxynicotinonitrile, and followed by reacting with dithiophosphoric acid 0,0-diethyl ester to prepare 2-hydroxythionicotinamide.

Reference Example 340 4-(Benzyloxy)butanamide was allowed to undergo the reaction with 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane-2,4-disulfide in THF to prepare 4-(benzyloxy)butanethioamide.

Reference Example 347 A 4 M hydrogen chloride/EtOAc solution was added to 6-methoxypyridazine-3-carbonitrile, and followed by reacting with dithiophosphoric acid 0,0-diethyl ester to prepare 6-methoxypyridazine-3-carbothioamide.

Reference Example 349 (S)-3-Hydroxypiperidine hydrochloride was subject to thioamidation using benzoylthioisocyanate in toluene to prepare N-{[(3S)-3-hydroxypiperidin-l-yl]carbonothioyl}benzamide.
Reference Example 364 N-{[(3S)-3-hydroxypiperidin-l-yl]carbonothioyl}benzamide was reacted with a methylamine-methanol solution in methanol to prepare (3S)-3-hydroxypiperidine-l-carbothioamide.
Reference Example 381 Furan-3-carbothioamide was allowed to undergo the reaction with 3-bromo-2-oxopropanoic acid ethyl ester in ethanol to prepare 2-(3-furyl)-1,3-thiazole-4-carboxylic acid ethyl ester.

Reference Example 425 Tetrahydro-2H-pyrane-4-carbothioamide was allowed to undergo the reaction with 3-bromo-2-oxopropanoic acid ethyl ester in ethanol. The reaction liquid was concentrated and the residue was allowed to undergo the reaction with pyridine and trifluoroacetic anhydride in 1,2-dimethoxyethane, to prepare 2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazolecarboxylic acid ethyl ester.

Reference Example 427 2-(2-Hydroxy-3-pyridinyl)-1,3-thiazole-4-carboxylic acid ethyl ester was allowed to undergo the reaction with phosphorus oxychloride to prepare 2-(2-chloro-3-pyridinyl)-1,3-thiazole-4-carboxylic acid ethyl ester.

Reference Example 428 1-j4-(Ethoxycarbonyl)-1,3-thiazol-2-yl]piperidine-4-carboxylic acid was allowed to undergo the reaction with CDI in THF, and then 28% aqueous ammonia was added thereto to prepare 2-[4-(aminocarbonyl)piperidin-1-yl]-1,3-thiazole-4-carboxylic acid ethyl ester.

Reference Example 431 6-Methoxypyridine-3-carbothioamide hydrochloride was allowed to undergo the reaction with 3-bromo-2-oxopropanoic acid ethyl ester in ethanol to prepare 2-(6-hydroxy-3-pyridinyl)-1,3-thiazole-4-carboxylic acid ethyl ester.
Reference Example 437 {[(2R)-2-Amino-3-hydroxypropanoyl]amino}acetic acid methyl ester was allowed to undergo the reaction with acetic acid, benzaldehyde, and sodium triacetoxyborohydride in a mixed solvent of methylene chloride and DMF to prepare (6R)-1-benzyl-6-(hydroxymethyl)piperazine-2,5-dione.
Reference Example 439 [(2S)-1-Benzylpiperazin-2-yl]methanol was allowed to undergo the reaction with di-tert-butyl dicarbonate in a THF solution to prepare (3S)-4-benzyl-3-(hydroxymethyl)piperazine-l-carboxylic acid tert-butyl ester.

Reference Example 440 (3S)-4-Benzyl-3-(hydroxymethyl)piperazine-l-carboxylic acid tert-butyl ester was allowed to undergo the reaction with sodium hydride and methyl iodide to prepare (3S)-4-benzyl-3-(methoxymethyl)piperazine-l-carboxylic acid-tert-butyl ester.

Reference Example 442 (3S)-4-Benzyl-3-(methoxymethyl)piperazine-l-carboxylic acid tert-butyl ester was allowed to undergo the reaction with 10% palladium-carbon and formic acid in methanol to prepare (3S)-3-(methoxymethyl)piperazine-l-carboxylic acid tert-butyl ester.

Reference Example 448 Benzyl methyl(oxetan-3-yl)carbamate was allowed to undergo the reaction with palladium-carbon and a hydrogen gas in methanol, and then with a 0.4 M hydrogen chloridelEtOAc solution to prepare N-methyloxetan-3-aminehydrochloride.

Reference Example 449 2-Bromo-1,3-thiazole-4-carboxylic acid ethyl ester was allowed to undergo the reaction with 4-(hydroxymethyl)-4-piperidinol trifluoroacetate and potassium carbonate in DMF to prepare 2-[4-hydroxy-4-(hydroxymethyl)piperidin-l-yl]-1,3-thiazole-4-carboxylic acid ethyl ester.

Reference Example 456 Under an argon atmosphere, 2-bromo-1,3-thiazole-4-carboxylic acid ethyl ester was allowed to undergo the reaction with copper iodide (I), N,N-dimethylethane-1,2-diamine, potassium carbonate, and pyrrolidin-2-one in dioxane to prepare 2-(2-oxopyrrolidin-l-yl)-1,3-thiazole-4-carboxylic acid ethyl ester.
Reference Example 470 2-[3-(Benzoyloxy)-1,1-dimethylpropyl]-1,3-thiazole-4-carboxylic acid ethyl ester was allowed to undergo the reaction with sodium ethoxide in ethanol to prepare 2-(3-hydroxy-1,l-dimethylpropyl)-1,3-thiazole-4-carboxylic acid ethyl ester.

Reference Example 474 2-(Chloromethyl)-1,3-thiazole-4-carboxylic acid ethyl ester was allowed to undergo the reaction with 2-methoxy-N-methylethaneamine in DMF to prepare 2-{[(methoxyethyl)(methyl)amino]methyl}-1,3-thiazole-4-carboxylic acid ethyl ester.

Reference Example 475 2-(chloromethyl)-1,3-thiazole-4-carboxylic acid ethyl ester was allowed to undergo the reaction with 2-bromophenol and potassium carbonate in DMF to prepare 2-[(2-bromophenoxy)methyl]-1,3-thiazole-4-carboxylic acid ethyl ester.

Reference Example 476 A solution of 2-phenyl-1,3-thiazole-4-carboxylic acid ethyl ester in chloroform was allowed to undergo the reaction with N-bromosuccinimide to prepare 5-bromo-2-phenyl-1,3-thiazole-4-carboxylic acid ethyl ester.

Reference Example 477 5-Bromo-2-phenyl-1,3-thiazole-4-carboxylic acid ethyl ester was allowed to undergo the reaction with pyrrolidine to prepare 2-phenyl-5-(1-pyrrolidinyl)-1,3-thiazole-4-carboxylic acid ethyl ester.
Reference Example 554 A solution of 2-(4-hydroxy-l-piperidinyl)-1,3-thiazole-4-carboxylic acid in pyridine was allowed to undergo the reaction with acetic anhydride to prepare 2-[4-(acetyloxy)-1-piperidinyl]-1,3-thiazole-4-carboxylic acid.

Reference Example 555 1-(Aminocarbonothioyl)piperidine-4-carboxylic acid ethyl ester was allowed to undergo the reaction with sodium hydrogen carbonate and 3-bromo-2-oxopropanoic acid in dimethoxyethane to prepare 2-[4-(ethoxycarbonyl)piperidin-1-yl]-1,3-thiazole-4-carboxylic acid.

Reference Example 556 (2-Methoxyethyl)methylamine was reacted with potassium cyanate in a 6 M aqueous hydrochloric acid solution to prepare N-(2-methoxyethyl)-N-methylurea.
Reference Example 558 N-(2-Methoxyethyl)-N-methylurea was reacted with 3-bromo-2-oxopropanoic acid ethyl ester in ethanol to prepare 2-[(2-methoxyethyl)(methyl)amino]-1,3-oxazole-4-carboxylic acid ethyl ester.

Reference Example 564 2-[(tert-Butoxycarbonyl)amino]isonicotinic acid was allowed to undergo the reaction with L-serine methyl hydrochloride, WSC-HCl, HOBt, and triethylamine in DMF to prepare (2S)-2-({2-[(tert-butoxycarbonyl)amino]isonicotinoyl}amino)-3-hydroxypropionic acid methyl ester.
Reference Example 566 4-Pyridazinecarbonyl chloride was allowed to undergo the reaction with L-serine methyl hydrochloride and triethylamine in acetonitrile to prepare (2S)-3-hydroxy-2-[(pyridazin-4-ylcarbonyl)amino]propionic acid methyl ester.

Reference Example 577 (2S) -2- ( {2- [ (tert-Butoxycarbonyl)amino]isonicotinoyl}amino)-3-hydroxypropionic acid methyl ester was allowed to undergo the reaction with 2-methoxy-N-(2-methoxyethyl)-N-(trifluorosulfanyl)ethaneamine, and then with bromotrichloromethane and 1,8-diazabicyclo[5.4.0]-7-undecene in methylene chloride to prepare 2-{2-[(tert-butoxycarbonyl)amino]pyridin-4-yl}-1,3-oxazole-4-carboxylic acid methyl ester.

Reference Example 592 2-[(2R)-Pyrrolidin-2-yl]-1,3-oxazole-4-carboxylic acid methyl ester was allowed to undergo the reaction with acetic anhydride and pyridine in dichloromethane to prepare 2-[(2R)-1-acetylpyrrolidin-2-yl]-1,3-oxazole-4-carboxylic acid methyl ester.

Reference Example 593 2-(4-{[tert-Butyl(dimethyl)silyl]oxy}cyclohexyl)-1,3-oxazole-4-carboxylic acid methyl ester was allowed to undergo the reaction with tetra n-butylammonium fluoride in THF to prepare 2-(4-hydroxycyclohexyl)-1,3-oxazole-4-carboxylic acid methyl ester.

Reference Example 596 2-Chloro-1,3-oxazole-4-carboxylic acid ethyl ester was allowed to undergo the reaction with 3-furylboronic acid, tetrakistriphenylphosphine palladium (0), and an aqueous potassium carbonate solution in toluene to prepare 2-(3-furyl)-1,3-oxazole-4-carboxylic acid ethyl ester.

Reference Example 600 2-Vinyl-l,3-oxazole-4-carboxylic acid ethyl ester was allowed to undergo the reaction with N-benzyl-l-methoxy-N-[(trimethylsilyl)methyl]methaneamine and trifluoroacetic acid in toluene to prepare 2-(1-benzylpyrrolidin-3-yl)-1,3-oxazole-4-carboxylic acid ethyl ester.

Reference Example 601 1,3-Oxazole-4-carbonyl chloride was allowed to undergo the reaction with 2-amino-2-methyl-l-propanol and triethylamine in methylene chloride to prepare N-(2-hydroxy-1,1,-dimethylethyl)-1,3-oxazole-4-carboxamide.
Reference Example 602 N-(2-Hydroxy-l,1-dimethylethyl)-1,3-oxazole-4-carboxamide was allowed to undergo the reaction with thionyl chloride in methylene chloride to prepare 4,4-dimethyl-4,5-dihydro-2,4'-bi-1,3-oxazole.
Reference Example 603 4,4-Dimethyl-4,5-dihydro-2,4'-bi-1,3-oxazole was allowed to undergo the reaction with n-butyllithium, benzaldehyde in THF to prepare (4,4-dimethyl-4,5-dihydro-2,4'-bi-1,3-oxazole-2'-yl)(phenyl)methanol.
Reference Example 604 (4,4-Dimethyl-4,5-dihydro-2,4'-bi-1,3-oxazole-2'-yl)(phenyl)methanol was allowed to undergo the reaction with methyl iodide, and then with a 2 M aqueous sodium hydroxide solution to prepare 2-[hydroxy(phenyl)methyl]-1,3-oxazole-4-carboxylic acid.

Reference Example 605 2-Morpholin-4-yl-1,3-oxazole-4-carboxylic acid ethyl ester was allowed to undergo the reaction with 1.7 ml of a 1 M aqueous sodium hydroxide solution in ethanol for performing hydrolysis to prepare 2-morpholin-4-yl-1,3-oxazole-4-carboxylic acid.

Reference Example 629 2-(6-Methoxypyridin-3-yl)-1,3-oxazole-4-carboxylic acid methyl ester was allowed to undergo the reaction with 48% hydrobromic acid in ethanol, and then with a 4 M
aqueous sodium hydroxide solution in methanol to prepare 2-(6-oxo-l,6-dihydropyridin-3-yl)-1,3-oxazole-4-carboxylic acid.

The structures and the physiochemical data of the compounds of Reference Examples 1 to 629 are shown in Table 5. In addition to the description on the preparation methods in Reference Examples as above, the compounds of the Reference Example Nos. were prepared in the same manner as the methods of Reference Examples of the numbers shown in Syn of Tables, using each corresponding starting materials.

In the tables of Reference Examples as described later, the following abbreviations are used.

Rex in the left-hand columns in the Tables represents Reference Example No., and the Str cells in the middle columns show the structural formulae of Reference Example compounds. The structural formulae marked with * in the cells of the tables indicate that the compounds are optically active. The tops in each cell of in the right columns show the Reference Example Nos. with reference to the preparation methods as Syn. For example, "27->14" as described in the preparation methods means that the same preparation method as in the preparation method of Reference Example 27 is performed, and then the same preparation method as in the preparation method of Reference Example 14 is performed. The materials horizontally described in the right hand of Syn, that is, (Sal) represents salts, and the materials without such a description represents free compounds. (HC1) represents hydrochloride, (Na) represents a sodium salt, (HBr) represents a hydrobromide, and (CF3CO2H) represents a trifluoroacetate. At the bottoms in the right columns show values by mass analysis as Dat (physiochemical data).

However, in Reference Example 424 and Reference Example 553, NMR data are shown.

[Table 5]

REx Str Syn (Sal) Me 8 Dat 8 dS MS(FAB) m/z:
OO NO2 1 02 220 ([M+H]+) F S' MS(FAB) m/z: F 9 F O F F 308 ([M+H]+) 9 N F ~~ N02 MS(ESI) m/z:
~
02 199 ([M+H]+) O / ~ 1 F 10 2 MS(FAB) m/z: N02 F 10 N MS(ESI) m/z:
F F 0 MeO 302 ([M+H]+) F CI 231([M-H] ) NO2 1 F ~ CI 11 o` -O 11 FO NO 2 MS(ESI) m/z:
3 F MS(ESI) m/z: F F C I F 367([M+H]+) 223([M+H]+) Br CI

NO 12 Me~ I MS(EI) m/z:

O/\ 1 O N 188([M]+) 4 F FF - F S,,o MS(ESI) m/z: O C~ 13 F~ 355([M+H]+) 13 / NO MS(EI) m/z:
F Me~N z NO2 188([M]+) Me * 14 o o 1 O"S F 0 MS(FAB) m/z: 14 BoC~ MS(FAB) m/z:
F' ~ Br Me 381([M+H]+) Me ~ONH2 272 ([M+H]+) OH Boc CONH2 15 10,442 15 N MS(FAB) m/z:
6 NO2 MS(EI) m/z: Me 272 ([M+H]+) O 181([M]+) Boc Me N j2 16 N N
MS(FAB) m/z:
7 ~"SO - O MS(FAB) m/z: CONH2 272([M+H]+) ~F 313([M+H]+) Boc i Me 15 F
17 MS(FAB) m/z:
CONH2 258([M+H]+) Boc \ Me 15 N02 27 18 N N MS(FAB) m/z: 28 C~LQH MS(ESI) m/z:
CONH2 286([M+H]+) 0 222 ([M+H]+) Boc OH 19 N O
19 N MS(FAB) m/z: ~ ~
CN 29 c MS(FAB) m/z:
241([M+H]+) 308 ([M+H]+) C02Me 20 (HCI) HZNOC
20 HN("X MS(FAB) m/z:

d-OCONH2 174([M+H]+) 30 MS(FAB) m/z:
21 (2HCI) 251 ([M+H]+) 21 H`-' CONH2 MS(ESI) m/z: 02 27 144 ([M+H]+) 31 F~~ ~ MS(FAB) m/z:
Me ~[c 21 (2HCI) H2NOC 283 ([M+H]+) 22 H ~ONH MS(FAB) m/z: O 27 Me 2 172 ([M+H]+) ~ ~
32 Me _ MS(FAB) m/z:
H N Me 21 (2HCI) H2NOC 279 ([M+H]+) 23 MS(FAB) m/z: is CONH2 172([M+Fi]+) Me 33 MS(FAB) m/z:
N 21 (2HCI) Me H NOC 279 ([M+H]+) 24 HN~ MS(ESI) m/z: 2 CONH2 158([M+H]+) 0 2 27 /-~
HN 21 (2HCI) 34 MS(FAB) mlz:
H2NOC 283 ([M+H]+) 25 Me/ N CONH2 MS(FAB) m/z:
172([M+H] ) CONH2 MS(ESI) m/z:
Me 21 (2HCI) :JlNO2 26 N' MS(ESI) m/z: ~N-Me 265 ([M+H]+) LCONH2 186([M+H]+) NO2 /

N~ 27 ~--~ ~
27 MS(FAB) m/z: 36 V__Z+
C02Me ~ 337 MS(ESI) m/z:
(IM+HI ) F H2NOC 283 ([M+H]+) H2NOC

Oz Me NO 2 37 CNH MS(FAB) m/z: 45 F N MS(ESI) m/z:
Me 2 293 ([M+H]) F H2NOC > 301 ([M+H]) NO2 H 2 Np 27 ~ NOZ

38 MS(API) m/z:
C Y
N~ 277 ([M-H] aN") -) 46 MS (FAB) m/z:
OZ O NH 305 ([M+H]+) ~
39 &N~\ 27 MS(ESI) m/z:
OH 253 ([M+H]+) OZ pH 27 Me, MS(ESI) m/z:
O2 225 ([M+HI+) 40 MS(ESI) m/z: Oz N~ 343 ([M+H]+) / \ ~ 27 H2NOC 48 MS(FAB) m/z:
Np 2 H2NOC 266 ([M+H]+) 41 MS(FAB) m/z: 27 N") 292 ([M+H]+) 49 N N MS(FAB) m/z:
9 H2NOC 269 ([M+H]+) Me-S NO2 NO2 42 ~-. MS(ESI) m/z: 50 F CN 27 327 ([M+H]+) CN MS(FAB) m/z:
H NOC H 308 ([M+H]+) 43 N") 27 ~, 27 F 30 m/z: 51 'j MS(ESI) m/z:
([ l ) 290 ([M+H]+) H N ~
P NO

'S -- NOZ
O ~ 27 N~ 27 44 N MS(ESI) m/z: 52 N MS(FAB) m/z:
t~A 344 ([M+H]+) Me02C C 323 ([M+H]+) H2NOC> H NO Z

02 27 C02Me 53 /MS(ESI) m/z: N02 27 _ O~COH H
N 254 ([M+H]+) 62 N MS(ESI) m/z:
322 ([M+H]+) N~ 02 27 'CONH2 54 N MS(FAB) m/z: NO2 286 ([M+H]+) 27 CONH2 63 Me0 MS(ESI) m/z:
O 27 H2NOC 295 ([M+H]+) 2 55 m/z - ~~ +H]) . 2 CI CN H2NOC 324 ([M 27 64 F N~N MS(FAB) m/z:
CI 02 27 H2NOC 283 ([M+H]+) MS(FAB) m/z: p 2 27 H NOC 299 ([M+H]+) 2 65 a~H MS(EI) m/z:
N02 219 ([M]+) 57 0 2 Me 27 CI ~N MS(FAB) m/z:
H2NOC 299 ([M+H]+) 66 11 H MS(ESI) m/z:
NO g 236 ([M+H]+) r\ N~ 27 02 Me 27 58 MS(ESI) m/z:
Br 343 ([M+H]+) 67 "-BoC MS(FAB) m/z:
HzNOC Me * 336 ([M+H]+) Oz 27 OH NO

59 + ~ MS(FAB) m/z: 27 CONH 68 MS(ESI) m/z:
2 267 ([M+H]+) H2NOC 293 ([M+H]+) O 2Q_Boc 27 0 27 60 MS(FAB) m/z: 2 69 / MS(ESI) m/z:
* C02Me 366 ([M+H]+) 205 ([M+H]+) 61 /\ - "-BOC MS(FAB) m/z: 70 ~` ~, MS(API) m/z:
~k C02Me 366 ([M+H]+) ~ 191 ([M+H]+) 02 27 ~ 27 71 MS(FAB) m/z:
81 N MS(EI) m/z:
CO2Et 279 ([M+H]+) ~ N02 235([M]+) 02 27 < CONH2 27 72 MS(ESI) m/z: N~1 NO2 CONH2 82 N r MS(EI) m/z:
250 ([M+H]+) N ~ F 283([M]+) jO_Me 27 CONH2 MS(ESI) m/z: NNO2 27 83 ,N /~ MS(EI) m/z:
OH 252 ([M+H]+) N' 283([M]+) 74 MS(ESI) m/z: NO2 C02Et 279 ([M+H]+) 84 N tN~ MS(EI) m/z:
268([M]+) 75 ~ MS(ESI) m/z: CONH

EtOZC 293 ([M+H]+) N'~ NO
85 ~,N / I MS(ESI) m/z:
02 27 Br F 361([M+H]+) 76 Q MS(ESI) m/z:

OH 223 ([M+H]+) 86 HO~N MS(API) m/z:

CO Me 281([M+H]+) 77 MS(API) m/z: 2 ~02Me 237 ([M+H]+) CONH2 9_Me 27 87 MS(ESI) m/z:
78 MS(ESI) m/z: F 361([M+H]) Br 236 ([M+H]+) 02 27 * N O2 27 N~
79 MS(API) m/z: 88 MS(FAB) (FAB) m/z:
CO2Me 251 ([M+H]+) HO' 223([M+H]+) CONH2 ~ / 27 /N 27 80 <N N N02 MS(FAB) m/z: 89 N C02Me MS(ESI) m/z:
Me 279([M+H]+) OH 282([M+H]+) 90 NN NO2 MS(FAB) m/z: 99 HO N N
MS(ESI) m/z:
i ~
271([M+H]+) 300([M+H]+) S C02Me CONH
2 ~
~N-\ N02 27 < CONH2 1 / 27 91 ~N Br MS(ESI) m/z: 100 ~ N NO2 MS(FAB) m/z:
Me N N 347([M+H]+) Me 293([M+H]+) Br ON', 27 ~ ~ 27 92 MS(FAB) m/z: 101 N / MS(FAB) m/z:
NO2 CO2Me 359([M+H]+) Me, NO2 OH ~CONH2 307([M+H]+) 93 ~,N MS(ESI) m/z:
N 102 Me N02 MS(ESI) m/z:
CI 300([M+H]+) N 293([M+H]+) ~O ~{c lp 94 N~ MS(FAB) m/z: 27 223([M+H]+) 103 CN MS(FAB) m/z:
N 171 ,448~27 H ~' N 02 209([M+H]+) 95 / N(~OH MS(FAB) m/z:
Br N O2 OH 254([M+H]+) 27 171-448~27 104 ` N MS(ESI) m/z:
96 `/ N` OH MS(EI) m/z: N NO
Z 343([M+H]+) NO2 OH 252([M]+) CONH z 97 N4~O MS(FAB) m/z: 105 N MS(FAB) m/z:
N02N 237([M+H]+) 280([M+H]+) NO2 ~ ~ ~ 27 CO2Et N N F CO2Et 98 HO/~' ~ MS(ESI) m/z:

C02Me 300([M+H]+) N
106 ~ Z MS(FAB) m/z:
\ ~ 297([M+H]+) F

107 ~,N MS(ESI) m/z: 115 N_ NO
2 MS(ESI) m/z:
CN 304([M+H]+) N /
` 276([M+H]+) CONH CN
N.~ 2 NO2 27 CONH2 108 N MS(FAB) m/z: 27 F~ CN 322([M+H]+) 116 r,NOz MS(FAB) m/z:
NC02Me 309([M+H]+) ~ 27 109 N N MS(FAB) m/z:
285([M+H]+) 117 N NO 2 MS(FAB) m/z:

CONH 285([M+H]+) -N

110 N~ NO2 MS(ESI) 27 m/z: CI C02Me Na 27 N Br 344([M+H]+) 118 N OH MS(ESI) m/z:
~ NH2 27 L3NO2 296([M+H]+) N~ NO2 111 ~N MS(ESI) m/z: CO2Et 27 N ~ CI 300([M+H]+) 119 ~N N02 MS(ESI) m/z:
CONH2 CI 313([M+H]+) 112 MS(ESI) m/z: NO2 27 N, ( Me 280([M+H]+) 120 * Z~N, MS(ESI) m/z:
CO N H2 HO--' N= 240([M+H]+) 27 C02Et 113 Oki NO2 MS(FAB) m/z: NO2M e N 121 N~ MS(ESI) m/z:
= / Br 329([M+H]+) ~ ~ ~ 309([M+H]+) 27 ~N~ 27 114 r, NO2 MS(ESI) m/z: 122 ~,~N ~ CF3 MS(ESI) m/z:
N. / 265([M+H] ) p Me NO2 349([M+H]+) CONH2 ~ 132 ON N02 27 132 CN ~~ NH 2 MS(EI) m/z:
123 \ MS(FAB) m/z: ~ 258[M]-) N 281([M+H]+) Me-O CO2Et NO 27 N MS(ESI) m/z:

L
27 N - 2Me 294([M+H]+) 124 ON,Me MS(FAB) m/z: l NHZ 27 N O 281([M+H]+) 134 ON N02 CHF MS(ESI) m/z:

I ' 2 331 M+H +
HN-Boc O ([ ] ) 125 N MS(FAB) m/z: MS(FAB) m/z:
336([M+H]+) 135 -Boc 323 ([M+H]+) N'~ N 02 27 i oc N O2 135 126 ~,N I MS(ESI) m/z: 136 N MS(FAB) m/z:
Cl 356([M+H]+) 319([M+H]+) CN F
~ Boc 135 MS(FA
B) m/z:
N 0~N 27 137 C/~-d 127 MS(ESI) m/z: 319([M+H]+) O NO2 250([M+H]+) Boc N'--) NO2 128 N NO2 135 128 ~N ~ Me MS(ESI) m/z: 138 MS(ESI) m/z:
Br ~ O 318([M+H]+) F~ F 341([M+H]+) C0LN~ Et NO 27 Boc NO 2 129 ~ I 2 MS(ESI) m/z: 139 N/ MS(ESI) m/z:
N'~ F 298([M+H]+) F F 341([M+H]+) CF3 Boc 130 Boc ,O N NH2 140 130 O"S`O C MS(ESI) m/z: 140 N \ ~\ MS(FAB) m/z:
368([M+Na]+) 300([M+H]+) Boc CN
CF 3 O N' 130 Boc N H2 140 131 O,S" MS(ESI) m/z: 141 N MS(FAB) m/z:
O 368([M+Na]+) CN 312([M-H]-) 02 Me 21 02 14 142 /\ N~N H MS(FAB) 152 MS(FAB) m/z:
- ~J 236 ([M H] ) ([M+H]+) Me~ H2NOC
~k zNOC
02 21(CF3CO2H) 02Me 14 (_4,J\1H MS(ESI) m/z: N N
143 223 ([M+H]+) 153 ~--( ONH MS(FAB) m/z:
z 293 ([M+H]+) F Me 1~
H N N 02 21 (HCI) 02~ - ,Me ~c 14 144 MS(ESI) m/z: 154 -~~~ MS(FAB) m/z:
219([M+H]}) Me' H2NOC 293 ([M+H]+) H2Nf 21 02 14 145 HNo MS(EI) m/z: 155 KII-\ MS(FAB) m/z:
F 192([M]+) D
280 ([M+H]+) NH
146 MS(Ei) m/z: CN;~ z NOz 14 NH2 199([M]+) 156 ~-,N i ~ Me MS(ESI) m/z:
CN NH 21 Br O 375([M+2H]+) 147 MS(EI) m/z: CONHz NO 14 N H2 213([M]}) 2 157 MS(ESI) m/z:
F F ~ N H 21 (HCI) O 307([M+H]+) 148 ~ ~ MS(ESI) m/z:
NO2 241QM+H]+) ~o ONH2 NOz 14 MS(ESI) mlz:
158 ~
C NH 21 (HCI) - F 298([M+H]+) MS(ESI) m/z: F

aND 2 219([M+H]+) ~CONH2 NOz 14 N
F ~ NH 21 (HCI) 159 1 MS(FAB) m/z:
150 MS(ESI) m/z: 276([M+H]+) F~ NOz 241([M+H]+) ~ ONH2 NO2 14 Oz 14 160 N ~ - MS(FAB) m/z:
151 MS(ESI) m/z: 276([M+H]+) H2NOC 265 ([M+H]+) ~ ONH2 CONH2 NH2 14 N~ NO2 27-~14 N, MS(EI) m/z: 170 ~N ~ ~ Me MS(ESI) m/z:
F 249([M]+) ~ O 295([M+H]+) 162 N MS(ESl) mlz: 171 K:c-'c:cOH MS(API) m/z:
257([M+H]) CN 225 ([M+H]+) CONH2 (j-t.k'uOH 02 171 NH2 14 172 MS(ESI) m/z:
163 MS(ESI) m/z: OH 239 ([M+H]+) CN 271([M+H]+) CONH2 NO2 173 NHZ 14 173 ~--~N F MS(ESI) m/z:
164 CONH2~~, ~ MS(Ei) m/z: CN 308([M+H]+) N
233([M]}) CO2Me NO2 174 ~ONH2 174 \\N \ / MS(ESI) m/z:
N NO2 14 343([M+H]+) 165 MS(EI) m/z: Br F F 297([M]+) O2Et 175 NO2 MS(FAB) m/z:
02 27-+14 175 363 ([M+H]+) 166 n MS(ESI) m/z:
297 ([M+H]+) H2NOC >

O2~ 27-+14 MS(FAB) mlz:
167 ~N MS(ESi) mlz: 176 CONH2 221 ([M+H]+) 279 ([M+H]+) Hz 176 ~ MS(FAB) m/z: 177 ~ f ~H MS(ESI) m/z:
168 MeO ~ H NOC ) `~0 192 ([M+H]+) 296 ([M+H]+

CONHZ NO 27-~14 176 169 ~N ~~ 2 MS(ES!) m/z: 178 MS(ESI) m/z:
H NOC 235 ([M+H]+) N- 280([M+H]+) 2 CO2Me F H2 176 NHZ 176 188 ~~ MS(FAB) miz:
179 N MS(FAB) m/z: H2NOC 253 ([M+H]+) 278 ([M+H]+) CONH2 HZNO Hz 176 CO Me r\v z 189 MS(FAB) m/z:
-- i NHZ 176 Me 235 ([M+H]+) 180 N MS(FAB ) m/z:
292 ([M+H]t) H2 176 2 190 MS(FAB) m/z:
H2 176 F H2NOC 253 ([M+H]+) 181 -Boc MS(FAB) m/z: OzEt 275 ([M+H]+) H i I H2 176 2 176 191 MS(ESI) m/z:
182 IDCONH2 MS(FAB) m/z: 335 ([M+H]+) 221 ([M+H]+) H2NOC

H2~ 176 NHZ 176 183 F/\MS(ESI) m/z: 192 ' ON
MS(ESI) m/z:
H2NOC 253 ([M+H]+) COzMe 3 07 M+H
HzNO~ ([ ]+) ~-~ Ha 184 Me /MS(FAB) m/z: 176 - H2NOC 249 ([M+H]+) 193 MS(FAB) m/z:
H HZNOC 247 ([M+H]+) z 176 185 MS(FAB) m/z: 2 176 194 MS(FAB) m/z:
Me H2NOC 249 ([M+H]+) O~Ae~ONH2 263 ([M+H

]+) H2 176 H2 jVle * 176 186 MS(ESI) mlz: 195 MS(FAB) mlz:
F H2NOC 253 ([M+H]+) Me CONHZ 263 ([M+H]+) H2 176 H2 Me ~[t 176 1--1 j--Z
187 MS(FAB) m/z: 196 K '{ f~~ MS(FAB) m/z:
MeOV H2NOC 265 ([M+H]+) MeI-' ONHZ 263 ([M+H]+) 197 N, MS(FAB) m/z: 207 H2N ~ / MS(FAB) m/z:
H2NOC 249 ([M+H]+) H2NOC 314 ([M+H]+) 2/--\ 176 198 c~ f~1-Boc MS(FAB) m/z: 208 MS(FAB) m/z:
~k iO2Me 336 ([M+H]+) H NOC 271 +
F F 2 ([M H]+) ~--~ ~N H2 199 "-Boc MS(FAB) m/z: N 176 CO 2 Me 336 ([M+H]+) 209 MS(FAB) m/z:
~k H2 176 ~N H 275 ([M+H]+) 200 cOH MS(ESI) m/z: H2 176 OH 209 ([M+H / ]+) 210 \ ~N MS(ESI) m/z:
H2 H2NO 176 F H2NOC 267 ([M+H]+) ~
201 ~ MS(API) m/z: H2 OH 176 O 247 ([M-H]-) 211 /\ nl~ MS(ESI) m/z:
H2 OH 176 OH 195 ([M+H]+) 202 c ~ MS(ESI) m/z: H2 176 OH 223 ([M+H]+) H 212 N ~~~ MS(FAB) m/z:
2 176 H2NOC 236 ([M+H]+) 203 Me_~- MS(ESI) m/z: F NH2 H2NOC 313 ([M+H]+) \ 176 213 N MS(EI) m/z.
cH2 176 H2NOC 238 ([M]+) 204 ~~O MS(FAB) m/z:
H

262 ([M+H]+) H 2 176 214 MS(FAB) m/z:
205 O~ MS(ESI) m/z: F CN H2NOC 276 ([M-H] ) Me H2NOC 297 ([M+H]+) H2 176 Hz 176 215 - N MS(ESI) m/z:
206 F/\ N~> MS(ESI) m/z: OMe HZNOC 266 ([M+H]+) F H2NOC 271 ([M+H]+) H2~ 176 H2 176 216 NC " MS(ESI) m/z: 226 Q MS(ESI) m/z:
H2NOC/ 260 ([M+H]+) CO2Et 249 ([M+H]+) 217 MS(FAB) m/z: 227 MS(ESI) m/z:
MeO2C H2NOC 293 ([M+HI+) EtOZC 263 ([M+H]+) 218 H c MS(ESI) m/z: 228 MS(API) m/z:
N OH 224 ([M+H]+) OQ H 193 ([M+H]+) Hz ~ 176 H2 176 219 ~ ND CONH MS(FAB) m/z: 229 Na MS(ESI) m/z:
2 222 ([M+H]+) COZMe 207 ([M+H]+) 220 N~ MS(FAB) m/z: 230 J~I-Me MS(ESI) m/z:
C CN H2NOC 294 ([M+H]+) O206 ([M+H]+) 221 /\ i~ MS(ESI) m/z: ~ ~
231 N~ MS(FAB) m/z:
C02Me 221 ([M+H]+) N CONH2 239([M+H]+) 222 c~ MS(FAB) m/z: ~ ONH2 176 COZEt 249 ([M+H]+) 232 ~N NH2 MS(FAB) m/z:
H2 176 N F 254([M+H]+) 223 NDMS(ESI) m/z: CONH2 CONHZ 220 ([M+H]+) N,-) N 176 H2 OH 176 233 N ~ MS(ESI) m/z:
F
224 MS(ESI) m/z: CN 278([M+H]+) OH 195 ([M+H]+) 225 ~-Me MS(FAB) m/z: 234 HO N NH2 MS(API) m/z:
222 ([M+H]+) CO 2 Me 251([M+H]+) H

NH2 176 CONH2 l~ 176 235 No MS(EI) m/z: 244 N N ~ MS(EI) m/z:
* HO-~ 192([M]+) Me NH2 262([M]+) 245 I N MS(EI) m/z:
236 HO N MS(ESI) m/z: M~
NH2 H2N 248([M]+) C02Me 252([M+H]+) CONH2 < NN NH
L~ NH2 176 (2HBr) ~
N 246 2Me MS(FAB) m/z:
237 ~,N e , Br MS(ESI) m/z: I
i ~ 265([M+H]+) Me~N N 317([M+H]+) NH2 176 (HCI) Me ~\ 176 238 MS(ESI) mlz: 247 ~ N ~ MS(ESI) m/z:

193([M+H]+) L-CONH 2 263[M+H]+) CONH

239 N N/ MS(ESI) mlz:
N-` 250([M+H]+) 248 Me N NH MS(EI) m/z:
~CONH2 2 276([M]+) 240 Q-N~o MS(EI) m/z: N~ 176 NH2 205([M]+) 249 N MS(FAB) m/z:
QN176 CO Et 2 250([M+H]) N MS (EI) m/z: 2 NH2 206([M]+) 176 Q OH 176 250 MS(FAB) m/z:
N,~ CO Et NH2 267([M+H]+) 242 OH MS(EI) m/z: 2 NH2 222([M]+) H2N
F ~ 176 N ON, CNMS(ESI) m/z:

243 NH OH MS(ESI) m/z: 274([M+H]+) C02Me 270([M+H]+) CO
NH CONH
4 N^) 2 NH2 176 252 MS(ESI) m/z:
N Me 249([M+H]+) 253 N, MS(ESI) m/z: 262 N MS(ESI) m/z:
'C-N~ Me 235([M+H]+) NH2 OH 210([M+H]+) 254 N, MS(ESI) m/z: 263 ~ C N MS(FAB) m/z:
N~ CN 245([M+H]+) HN 306([M+H]+) CONH
* NH2 OH 176 L N,~ NH2 176 255 - MS(FAB) m/z:
~ f N~, 264 ~,N MS(EI) m/z:
179([M+H]+) O 276([M]+) Ci 176 CO Et 176 256 N ~ MS(ESI) m/z: NH2 NH2 279 M+H + 265 N,(~ ~ MS(EI) m/z:
CO2Me (L l) ~ Me 263([M]+) CONH
2 NH2 176 COYN Et 176 257 MS(ESI) m/z: NH2 266 MS(EI) m/z:
F CN 292([M+H]+) N,I F 267([M]+) 258 HO N N MS(ESI) m/z: 267 rN MS(ESI) m/z:
CO Me 266([M+H]+) N J NH2 301([M+H]+) N Me MS(EI) m/z: N N~ F

~ 268 HO MS(FAB) m/z:
250([M]+) ~
CONH2 C02Me 270([M+H]+) ~ CF3 176 ~ ONH2 NH2 176 260 ~N MS(ESI) m/z: N N
269 MS(FAB) m/z:
NL~ NH 2 319([M+H]+) N 254 M+H +
CONHz F ([ l ) - O CiNN OH 176 H2N ~/ Me 176 270 N~~OH MS(EI) m/z:
261 'N MS(ESI) m/z:
279([M+H]+) NH2 223([M]+) CO2Et H2 ,OH ~k 27-+176 CO2Et 278 271 MS(ESI) m/z: 280 N I MS(ESI) m/z:
OH 195 ([M+H]+) CI 282([M+H]+) H2 27-+176 272 ~~~`'~ MS(ESI) m/z: HzN ~ Me 278 ' \~ N J~
OH 179 ([M+H]+) 281 O MS(ESI) m/z:
Hz 27->176 CONH 2 251([M+H]+) 273 cOH MS(API) m/z: ~N NHz NH 278 207 ([M+H]+) N 2 N H2 176 282 ~ \ ti CI MS(ESI) m/z:
/~~ CN F 326([M+H]+) 274 \ N 1-OH MS(API) m/z:
N ~/ 194([M+H]+) CONH2 CO Et N~
2 NH 27-176 283 V-__,N MS(ESI) m/z:
275 F N 2 MS(ESI) m/z: Br M0 343([M+H]+) e N / 268([M+H]+) CONHz H2_ 284 (HCI) L N,.~ NH2 276 284 I~MS(FAB) m/z:
276 vN MS(ESI) m/z: 260 ([M+H]+) N CN 275([M+H]+) NC H2NOC

~ NH 27-~176-~284 Me Me CONH2 N. 2 HN Me ~ 277 285 l~,N MS(FAB) m/z:
277 N 0 N,/ MS(ESI) m/z: F CN 278((M+H]+) NH 349([M+H]+) H2 286 2 286 CI /N\~MS(ESI) m/z:
Br 278 H2NON 269 ([M+H]+) 278 N~ N NH MS(API) m/z: H2 286 < 2 313([M+H]+) 287 MS(FAB) m/z:
CONH2 - ~~
CI H2NOC 269 ([M+H]+) z H N'% CI 278 H2 286 279 MS(ESI) m/z: / \
288 MS(ESI) m/z:
CONHz 255([M+H]*) Br H2NOC 313 ([M+H]+) H2 H 2 N Br 286 ~ N ~ 286 289 Me0 ~ MS(EI) m/z: 298 <N MS(ESI) m/z:
H2NOC 261 ([M]+) CONH2 314[M+H]+) H H2N Tl~ Br 286 90 MS(EI) mlz: 299 N N MS(ESI) m/z:
F H2NOC 249 ([M]+) CONH2 299([M+H]+) CO
N NH2 NH 286 ~NNH2 NH2 286 291 ") 2 MS(ESI) m/z: 300 \ \ ~ MS(FAB) m/z:
241 ([M+H]+) 246([M+H]+) NH2 286 301 MS(FAB) m/z:
292 ~,N ~~ MS(ESI) m/z: 246([M+H]+) gr ~ F 331([M+H]+) CONH2 H2N \ ~ 286 302 N, F MS(ESI) m/z:
N~Br 268 M+H +
293 HO~ I MS(ESI) m/z: F (I ]) C/O~2Me 329([M+H]+) H2 H 2 N 286 303 N\ OCONH MS(F AB) m/z:
gr Z
294 QN MS(ESI) m/z: 221 ([M+H]+) C02Me 313([M+H]+) H2 304 H 2 N 304 MS(FAB) m/z:
F 286 N~Boc 262 ([M]+) 295 `N F MS(ESI) m/z: Hz 305 CONH2 268([M+H]+) 305 MS(ESI) m/z:
H N Ci CONH 206 ([M+H]+) 2 ~ 286 2 H
296 N N MS(EI) m/z: z 14 ~ ~ CONH 269([M]+) 306 MS(FAB) m/z:
2 i 260 ([M+H]+) H 2 N ~ CI N~~
~ 286 297 ~ IN N/ MS(EI) m/z:
CONH ONH2 254([M]+) N//-o H2 316 (2HCI) ~N
14 316 /\ \ H MS(FAB) m/z:
307 N f--"~ N MS(FAB) m/z: 175 ([M+H]+) r Ir 261([M+H]+) H
' N H2 2 316 (2HCI) Br 317 F/ H MS(FAB) m/z:
308 193 ([M+H]+) 308 Nu CF3 MS(FAB) m/z: H

0 269([M+H]+) 318 c\ \ H MS(ESI) m/z:
O~CF3 309 OMe 205 ([M+H]+) 309 MS(FAB) m/z: Z 14 ~NH
-Boc 389 ([M+H]+) 319 MS(FAB) m/z:
HO 232 ([M+H]+) -Boc H2NOC

310 N MS(ESI) m/z: H2 14 ~ N CF 3 F/ \ MS(FAB) m/z:
H 0 390([M+H]+) 320 H2NOC 250 ([M+H]+) O7\~CF3 309 NH MS(FAB) m/z: H2 14 F/\~ 407 ([M+H]+) 321 /_\ \ MS(FAB) m/z:
HO Boc MeO H2NOC 262 ([M+H]+) 312 d -Boc MS(FAB) m/z: CONH
SI) m/z:
HO 293 ([M+H]+) 322 N MS(E
2 NHbl,-H2 312 233([M+H]+) 313 FMS(FAB) m/z: ~ONH2 NH323 HO Boc 310 ([M]+) 323 N MS(ESI) m/z:
cN N OH 312 HO N251(LM+HI) 314 MS(ESI) m/z: F/ H2 324 N H2 Boc 294([M+H]+) ~~ 1 O MS(FAB) m/z:
cCNH OH 21 (HCI) 324 N 306 ([M+H]+) 315 MS(ESI) m/z: `~
NH2 194([M+H]+) H2 325 (2HCI) Boc Me * 335 325 MS(FAB) m/z: 335 Ni~p\Me MS(CI) m/z:
HZNOC 234 ([M+H]+) H 190([M+H]+) Me H2 325 * p 336 326 F MS(EI) m/z: 336 N , Me MS(CI) m/z:
H NOC 251 ([M]+) ~ \\p 162([M+H]+) 2 Me H2N 325 H Me * 337 (HCI) 327 CN F MS(ESI) m/z: 337 Me-N 0 MS(FAB) m/z:
CONH2 252([M+H]+) Me 104([M+H]+) H2N Me-N M O * 337 (HCI) 325 338 ~-/ MS(FAB) m/z:
328 <N F MS(ESI) m/z: Me~ 104([M+H]+) CO N H2 252([M+H]+) 339 ?ONH2 NH2 325 339 H 2 N MS(FAB) m/z:
329 C N - MS(FAB) m/z: HO N 155([M+H]+) ~ ~ 248([M+H]+) ~ \ 340 , CI 566 340 ~S MS(ESI) m/z:
330 ~` MS(EI) m/z: NH2 208([M-H]-) CI 203([M]+) Me 340 ~\ p 564 341 O MS(API) m/z:
NH
331 ~ MS(ESI) m/z: 2 132([M-H]-) H2N O 194([M+H]+) c,-',O 34 /\ O 564 342 p~S MS(ESI) m/z:
332 MeO MS(ESI) m/z: MMe NH2 238([M+H]+) Me NH2 222([M+H]+) p 0 333 S p 333 H2N-I-Y~ p H MS(API) m/z: 343 MS(API) m/z:
~--~
Me 118([M+H]+) H 2 N Me 238([M+H]+) p M e 334 S 340 O
334 H2N0 MS(ESI) m/z: 344 H N -Boc MS(FAB) m/z:
222([M+H]+) 2 Me 259([M+H]+) H2N S CI 340 p 345 ~~ MS(FAB) m/z: s 349 ~ CI 220([M+H]+) 354 H Qlro MS(FAB) m/z:
0 333-~334-+ 306([M+H]+) 346 S O 340 MMe MS(ESI) m/z: O H
S

zN Me 274([M+Na]+) 0 ~-~
355 N O MS(ESI) m/z:
Me s 347 - H 279([M-H]-) 347 O\ MS(EI) m/z:
N-N NH2 169([M]+) O S O~Me S 347 356 N~N O ~ MS(ESI) m/z:
~
348 S MS(ESI) m/z: H ~, 293([M-H]-) H2N 160([M-H]-) O N
N~ `N~OH 349 N OH 349 357 _ H MS(ESI) m/z:
349 H MS(ESI) m/z: OH 279([M-H]-) 'k 263([M-H]-) 350 H N MS(ESI) m/z: 358 H N-\ MS(FAB) m/z:
* 265([M+H]+) ~k Me~ 01 265([M+H]+) 349 O S~- N~ Me 349 c N~ N O
351 H MS(ESI) m/z: 359 H jMe MS(FAB) m/z:
HO2C 293([M+H]+) Me 267([M+H]+) C"%H ~ O 349 O g ~Me 352 NH MS(FAB) m/z: N~ ~O\ 349 264([M+H]+) 360 H ; Me MS(FAB) m/z:
Me 267([M+H]+) 353 H N MS(FAB) m/z: * Os 349 HO 279([M+H]+) 361 I j N N,]`O MS(FAB) m/z:
j.~ 263([M+H]+) ~k 0 S ~ OH 364 NJ, N 349 372 H2N N MS(ESI) m/z:
362 H o MS ESI m/z: O
= ( ) 175([M-H]-) ~ Me'0 265([M+H]+) * S OH 364 Me, 373 H N N~:r MS(ESI) m/z:
* S 0 349 2 OH 175([M-H]-) 363 ~
MS(FAB) m/z: S 364 eN
H 295([M+H]+) 374 H~N ..,,,0 MS(API) m/z:
364 2 Me 161([M+H]+) 364 H 2 N~N MS(ESI) m/z: H N 364 161([M+H]+) 375 2 N~ MS(FAB) m/z:
364 Me\ 161([M+H]+) H N~N S
365 2 ~ MS(ESI) m/z: 1-1Me 364 *
161([M+H]+) 376 H2N N0\ MS(FAB) m/z:
~ 364 Me Me 163([M+H]+) 366 H 2 N N MS(ESI) m/z: ~/Me * 364 C02H 187([M-H]-) 377 H N MS(FAB) m/z:
364 Me ' Me 163([M+H]+) H~CN 0 367 2 MS(E SI) m/z: S 364 N" 158([M-H] ) 378 H2NN~;''\ MS(CI) m/z:
364 O 159([M+H]+) ~N
368 H N 2 MS(FAB) m/z: S O 364 OH 175([M+H]+) 379 * H 2 N N~ \Me MS(EI) m/z:
364 ~O 190([M]+) 369 H2N N~ ,O MS(FAB) m/z:
349~364 ~ Me 202([M+H]+) 380 HZN N'~~OMe MS(ESI) m/z:
S NMe Me OH 349,364 149([M+H]+) 370 MS(ESI) m/z: Et02C 381 Me 147([M-H]-) 381 ZO MS(FAB) m/z:
S
S O.Me 364 224 ([M+H]+) 371 AN~ MS(API) m/z:
"2N ~,O
191([M+"]+) EtO2C Br 381 EtO2 382 \ ~ MS(FAB) m/z: /~ 381 S 314 ([M+H]+) 392 S N MS(ESI) m/z:
EtO Me N 381 O2H 285 ([M+H]+) 383 \> d MS(FAB) m/z: EtO2 381 S 277 ([M+H]+) 393 L S ~
I- H MS(ESI) m/z:
CO2Et 256 M+H +
381 O ([ ] ) 384 MS(FAB) m/z: O2Et 381 NW 2 276 ([M]+) 394 trNMS(FAB) m/z:
EtO 2 381 S ~NI1/le 270 ([M+H]+) 385 NMS(ESI) m/z: CO2Et 381 N 236 ([M+H]+) 395 ~~
S Me MS(FAB) m/z:
Et02 381 0 298 ([M+H]+) 386 MS(FAB) m/z: CO Et S N 236 ([M+H]+) 2 N Me 381 EtO 2 381 396 MS(ESI) m/z:
S 228 M+H +
387 s NN MS(ESI) m/z: Me ([ ]) 236 ([M+H]+) Me Et0 C 381 2 N 431 397 N MS(ESI) m/z:
388 it~ MS(FAB) m/z: ~S 256 M+H +
S 0 H 251 ([M+H]+) CO2Et ([ ]) 2 Et Et02 OH 381 CO N 381 389 MS(ESI) m/z: 398 / ~ MS(ESI) m/z:
257 ([M+H]+) S 228([M+H]+) Et02 OH 381 CO2Et 381 390 MS(ESI) m/z: N
399 ~ MS(ESI) rn/z:
257 ([M+H]+) S 226([M+H]+) EtO 2 381 CO Et 391 S MS(FAB) m/z: N
HO 271 ([M+H]+) 400 MS(ESI) rn/z:
S S 258([M+H]+) CO2Et ~ 381 Boc O\
401 / N O I~ MS(ESI) m/z: N~ S Me 381 5~~~/ 411 ~N MS(FAB) m/z:
306([M+H]+) \~
* NC 386([M+H]+) C02Et 381 C02Et 402 k~ N O-Me MS(ESI) m/z: CO2Et 381 230([M+H]+) 412 N N O ; MS(ESI) m/z:
C02Et O 381 *\ Me" 257([M+H]+) 403 N O MS(API) m/z: C02Et S M~Me 334([M+H]+) N Boc 381 413 t - I MS(FAB) m/z:
N;N S N
381 Me 355([M+H]+) 404 N MeO MS(ESI) m/z: CO Et CI 381 CO Et 266([M+H]+) z 2 414 \ CI MS(FAB) m/z:
C02Et ~~ 381 S 316([M+H]+) 405 N O~ MS(ESI) m/z: C02Et 381 ~O
S Me 0 334([M+H]+) 415 NJ MS(FAB) m/z:
CO Et * S Me 381 Me 257([M+H]+) 406 ~>-N oH MS(API) m/z: C02Et Me * 381 N

S Me 245([M+H]+) 416 L\~r N ~ O, Me MS(FAB) m/z:
C02Et Me 259([M+H]+) 407 SO MS(ESI) m/z: C02Et Me ~C 381 Me Me 0 348([M+H]+) 417 \NOMe MS(EI) m/z:
C02Et O-Me 381 S Me 258([M]+) 408 N ~O MS(ESI) m/z: C02Et 381 O
N~ 287([M+H]+) 418 \N~ MS(FAB) m/z:
CO2Et OH 381 255([M+H]+) 409 LN 5:~O MS(ESI) m/z: CO2Et O~ 381 N c~ Me S 273([M+H]+) 419 N NIO MS(FAB) m/z:
COP OH 381 S 287([M+H]+) N
410 ~-N MS(ESI) m/z:
S
* =OH 273([M+H]+) Et02 349-->364 CO2Et f-CF3 308-+337 / 1 e ->381 N -349->364 420 SN~e ~ S
MS(API) m/z: 426 * O ~381 ~OMe 273 ([M+H]+) MS(ESI) m/z:
02Et 349->364 325([M+H]+) N -+381 EtO2C 427 421 S~N~CF3 V,_,,OMe MS(ESI) m/z: 427 S _ MS(FAB) mlz:
313 ([M+H]+) CI N 269 ([M+H]+) 02Et 349->364 OZEt ->381 428 422 g N 428 ~ O MS(ESI) m/z:
~OMe MS(FAB) m/z: S N\~
285 ([M+H]+) NH2 284 ([M+H]+) CO Et 2 i e Me 349,364 02Et 423 ~S ->381 ~ 564 S MS(API) m/z: 429 S N O MS(ESI) m/z:
261([M+H]+) 342 ([M+H]+) C 02 Et HO H
349-+364 N /> Me -->381 O2Et N
g \/'p NMR: (CDCI3) 564 S
0.79-0.92(4H, 430 MS(ESI) m/z:
m),1.36(3H,t,J 368 ([M+H]+) =7.1 Hz),2.69- HN,__o O
424 2=76(1 H,m), COZEt 3.33(3H,s), 431 3.67(2H,t,J= 431 I S \ O MS(EI) m/z:
N 250 ([M]+) 5.3Hz),3.83(2 H
H,t,J=5.3Hz), go~ O. 335 4.34(2H,q,J= 432 \N~ Me MS(ESI) m/z:
7.1 Hz),7.44(1 ~,O 231([M+H]+) H,s) N H
21 (HCI) C02Et 425 433 1 Me MS(ESI) rn/z:
425 N MS(ESI) m/z: Oy 132([M+H]+) O 242([M+H]+) H N OH 21 (HCI) ~~~-Me 21 (HCI) 434 _ MS(ESI) m/z: 444 N O , MS(ESI) m/z:
118([M+H]+) H * 116([M+H]+) CO2Me Boc 564 ~\ 335 N HN OH MS(FAB) m/z: 445 N,/j O
435 ` Me MS(ESI) m/z:
~k 0 277([M+H]+) 268([M+H]t) O TCO2Me 442 21 (HCI) 446 HN~ J ~Me MS(ESI) m/z:
436 >-NH MS(FAB) m/z: 102([M+H]+) NH2 ~k 177([M+H]+) O
OH
Me, N 336->440 HN''-~O i 437 447 O ~~ MS(ESI) m/z:
437 O~N MS(FAB) m/z: 0 ~ 244([M+Na]+) ---OH ~k 235([M+H]+) ~k HO- ~Me 448 _ 337 448 O H MS(FAB) m/z:
438 N MS(FAB) mlz:
NH 207([M+H]+) 88(LM+HI+) CO2Et 449 Boc OH I 439 449 ~ OH MS(ESI) m/z:
439 MS(FAB) m/z: S N`--' OH 287 M+H +
([ ] ) * 307([M+H]+) CO Et 2 * 449 Boc -Me O 440 450 N~
I ND MS(API) m/z:
440 N~ MS(FAB) m/z: S 'F 245([M+H]+) ~'N 21 M+H +
* 3 ([ ] ) CO2Et 449 0-Me 21 (2HCI) 451 Me MS(ESI) m/z:
441 HN~~ MS(FAB) m/z: 243([M+H]+) ~N~
* 221([M+H]+) CO Et 449 Boc O--Me 442 452 2 N~ N MS(ESI) m/z:
Y :
442 MS(FAB) m/z: *\ S Me 241([M+H]+) ~ N H * 231([M+H]+) CO2Et O 449 Me 440 453 ~N Me MS(API) m/z:
443 O MS(ESI) m/z: S 271([M+H]+) Boc ~k 216([M+H]+) * 449 C02Et CO2Et 8 N
454 N~N %O MS(EI) m/z: 464 / O MS(FAB) m/z:
Me 270([M]+) S -290([M+H]+) CO2Et Me 449 O
455 \NIjN, MS(ESI) m/z: COI Et 440 257([M+H]) 465 MS(API) m/z: CO2Et 0 456 S Me Me 244([M+H]+) 456 N N MS(ESI) m/z: CO2Et Oll Me 440 S 241([M+H]+) 466 I N MS(ESI) m/z:
~
S Me 244([M+H]+) EtO2C 449 457 ~~NDI MS(ESI) m/z: CO2 Et Me Me 440 \
S 225 ([M+H]+) 467 ~O/ MS(ESI) m/z:
S 216([M+H]+) 02Et OH 171 CO H 0-Me 440->605 458 ~~N~ MS(ESI) m/z: 2 MS(API) m/z:
S OH 259 M+H + 468 N
([ ] ) ~
S
CO 2 Et 8 Me 216([M+H]+) CO2Et O- Me 440 459 ~~ 0- MS(ESI) m/z: N
S 251 ([M+H]+) 469 ~~ MS(API) m/z:
02Et 8 S Me Me 258([M+H]+) 460 \ --N S=0 MS(ESI) m/z: C02EN Me Me 470 U 470 OH MS(ESI) m/z:
S 275 ([M+H]+) ~
02Et 8 ~ S 244([M+H]+) 461 \ N Sp MS(ESI) m/z: C02EV OH 442 S v O 291 ([M+H]+) 471 MS(API) m/z:
~
CO2Et Me O S,Me 8 S 216([M+H]+) OH
462 N\_j MS(API) m/z: C02EN 470 Me MS ESI m/z:
277([M+H]+) 472 ( ) ~ s Me 230([M+H]+) Me CO Et 470 CO2Et Me \O 8 2 Me OH
463 N\ N~ 'O MS(API) m/z: 473 N~J MS(ESI) m/z:
S 293([M+H]+) 230([M+H]+) CO2Et Me Me 474 HO2 605 474 N O MS(FAB) m/z: 484 ~ S + MS(FAB) m/z:
N -259([M+H]+) p 223 ([M+H]+) CO2Et Br 475 COZH 605 N~O ~ I FAB) m/z: 485 ~~ \ -O MS(ESI) m/z:
475 S MS(FAB) 342([M+H]+) 223 ([M+H]+) Et02C N 0-/l, 476 486 t ~}- (\ -MS(FAB) m/z:
476 MS(FAB) m/z: S ~N 208 ([M+H]+) Br S 314 ([M+H]+) HO2C 605 Et0 2 477 487 t -//N MS(EI) m/z:
477 [:~N s 1 MS(FAB) m/z: S N 207 (LMI+) 303 ([M+H]+) HO2C 605 HO CI 605 488 tN~ IV MS(ESI) m/z:

478 ~ MS(FAB) m/z: 208 ([M+H]+) S 240 ([M+H]+) HO2C 605 ~
HO C Br 605 489 ~ \ p MS(ESI) m/z:
2 b S
479 ~` MS(ESI) m/z: 196 ([M+H]+) S 286 ([M+H]+) HO 2 N 605 H0 2 C r 605 490 \-I~ MS(ESI) m/z:
S
480 > \ MS(FAB) m/z: 199 ([M+H]+) S 286 ([M+H]+) HOz 605 OZH 605 491 Srl~/ MS(ESI) m/z:
481 ~ NMe MS(FAB) m/z: * OH 215 ([M+H]+) S z HO 605 248 (LMl+) 2 02H 605 492 _N~~ MS(ESI) m/z:
* S OH 215 ([M+H]+) 482 ` \ O MS(FAB) m/z:

223 ([M+H]+) N pH
, HO C 493 I S}-~ MS(ESI) m/z:
2 605 OH 231 ([M+H]+) 483 tN~ MS(ESI) m/z: HO C 605 p H 223 ([M+H]+) 494 ~~--MS(FAB) m/z:
S
213 ([M+H]+) 495 -N~OH MS(ESI) m/z: 605 S ~J 229 ([M+H +
-'N~: ) 505 MS(ESI) mlz:
]
H02 605 "rO 340 ([M+H]+) 496 MS(ESI) m/z: O
* OH 229 ([M+H]+) HO C

HOZ 605 506 1~ ~ H MS(ESI) m/z:
497 ~ MS(ESI) m/z: S~ 228 M+H +
o ([ l) * OH 229 ([M+H]+) CO2H Me Me 605 70N H 605 507 ~~- ~~ O/Me MS(API) m/z:
OH MS(ESI) m/z: S
498 " 245 ([M+H]+) S OH 259 ([M+H]+) CO2H ~ 605 HO 2C I 605 508 1~- ~OMe MS(API) m/z:

S MS(ESI) m/z: S 257 ([M+H]+) 215 ([M+H]+) OzH 605 `-CF3 H02C 605 509 1~N OMe MS(ESI) m/z:
500 S ~~S MS(API) m/z: S ~/ 285 ([M+H]+) 229 ([M-H]-) HO2 605 C02H Cs=o 605 510 CN S~ MS(FAB) mlz:
501 MS(API) m/z: 273 ([M-H]-) 247 ([M+H]+) N
502 S ~O MS(API) m/z: 511 Me MS(ESI) m/z:
263 ([M+H]+) Me 200([M+H]+) 02H 605 Me 503 ~\ O MS(ESI) m/z: CO H 605 S NH2 256 ([M+H]+) 512 N2 MS(API) m/z:
CO2H s 228([M+H]+) ~ ~ 605 CO H

504 S N O MS(ESI) m/z: N O 605 NH 314 ([M+H]+) 513 ~ S MS(ESI) m/z:
HO7 ~/~ 214([M+H]+) C02H O 605 C02H Me pH 605 514 N~ MS(ESI) m/z: 524 ~NMS(ESI) m/z:
S 200([M+H]+) S 200([M-H]-) CO2H 605 CO2H N~ 605 f O MS(FAB) m/z:
515 MS(ESI) m/z: 525 NV
S 198([M+H]+) Me 229([M+H]+) Me CO2H S 605 CO H 1 p 605 516 N MS(ESI) m/z: 526 2N~N~-- ~ MS(FAB) mlz:
S 230([M+H]+) S 231([M+H]+) CO2H 19 605 Me Me 517 N S-O MS(FAB) m/z: CO2H OH 605 S 262([M+H]+) 527 MS(ESI) m/z:
CO~H OH 605 S 214([M-H]-) 518 1 N.~ MS(API) m/z: C02H ~~Me 605 S 188([M+H]+) 528 N MS(ESI) m/z:
CO2H p~Me 605 \N ~
S ~~ 259QM+FiI+) 519 ~ MS(ESI) m/z: CO 2 H OH 605 S 202([M+H]+) 529 ~N
N p MS(ESI) m/z:
C02H Me Me 605 S ~ 245([M+H]+) 520 p' MS(API) m/z:
188([M+H]+) CO H* OH 605 CO2H Me 605 530 2N N~ MS(ESI) m/z:
521 ~N O/ MS(API) m/z: S 0H 245(LM+H]+) S~Me Me 216([M+H]+) Me-O

CO\NMe H OH 605 Boc 531 ~NN N , MS(FAB) mlz:
522 , MS(ESI) m/z: 358 M+H +
~(c HO2C ([ ] ) S Me 202([M+H]+) S N=N C02H 605 532 O MS(ESI) m/z:
523 O MS(ESI) m/z:
N / S Me 229([M+H]+) CO2H Me 238([M+H]+) CO2H N-B e 605 CO2H r--'O 605 533 N_ Me MS(ESI) m/z: 542 \ N MS(ESI) mlz:
S 325([M-H]-) * S Me 229([M+H]+) CO2H Br ~ I CO2H Me O.Me 605 605 , 534 NO \ MS(FAB) m/z: 543 NYN~ MS(FAB) m/z:
S 314([M+H]+) S Me * 231([M+H]+) CI CO2H Me O~Me 605 544 NYN~ MS(EI) m/z:
535 /N CI MS(FAB) m/z: Me * 230([M]+) S 288([M+H]+) CO2H Me 605 545 N` No .,O MS(FAB) m/z:
536 N N~ O MS(ESI) m/z: \ S Me' 243([M+H]+) S 215([M+H]+) 2 605 546 Nr,-~ MS(FAB) mlz:
537 ~ N MS(ESI) m/z: *\ S 227([M+H]+) S~ 213([M+H]+) O
CO 2H , Me 605 CO2HN 605 547 * N MS(FAB) mlz:
538 ND MS(ESI) m/z: N O
S ~ 259([M+H]+) * S Me 213([M+H]+) TS H 381~605 CO2H 605 N >~~e (HCI) ~
539 N MS(ESI) m/z: 548 ~ - I~OMe MS(ESI) m/z:
~c \ S F 217([M+H]+) 217 ([M+H]+) 0 605 COYS H 381-~605 COZH Me ~ H (HBr) 540 N N MS(ESI) m/z: 549 OMe ~ MS(ESI) m/z:
~
243([M+HI+) 203 ([M+H]+) C02H Me 605 CO2H Boc 381->605 541 N MS(EI) m/z: N
228([M]+) 550 MS(ESI) m/z:
S N 311 ([M-H]-) CO2H p,Me 440-605 O2Et e 558 551 N MS(ESI) m/z: 558 t N}- ~ OMe MS(ESI) mlz:
S Me Me 230([M+H]+) O~ 229 ([M+H]+) 02 Et 558 N 559 MS(ESI) m/z:
~~
552 Ls \N p.Me MS(ESI) m/z: p OH 241 ([M+H]+) ~-j 243([M+H]+) Et0 C
z 558 C02H Me Me 349-364-560 Cl~No MS(ESI) m/z:
\ N~ N~p 381-+605 225 ([M+H]+) S Mex (HCI) COL Et 558 NMR: O

(DMSO-d6) M~ MS(ESI) m/z:
p CO2Et 270([M+558H]+) 1.08(3H,d,J=
553 5.9Hz),3.07(3 _~C O MS(ESI) m/z:
H,s),3.24(3H,s 562 , N`
),3.45(2H,d,J= 0 226([M+H]+) 6.OHz),3.64(1 0 605 H,dd,J=5.9,6.0 563 TBS CO2H MS(ESI) m/z:
Hz),7.53(1 H,s) 257([M-H]-) ,11.77(1 H,brs) BocHN
02H 554 p ~ 564 554 ~~R(~ OAc MS(FAB) m/z: 564 Hp-,~ MS(FAB) mlz:
S `--' 271 M+H + H 340([M+H]+) ([ ] ) MeO2C ~t 02H 555 OMe 555 S-11-CO2Et MS(FAB) m/z: N 564 285 ([M+H]+) 565 MS(ESI) m/z:

O CO Me * 255 ([M+H]+) H N'~~OMe 556 H 2 556 2 , MS(ESI) m/z:
HO
Me 133([M+H]+) '-- 566 0 O Me 566 MeO2CH ~~ MS(ESI) m/z:
557 H2N ~Na v 556 MS(ESI) m/z: ~c ~~ 226 ([M+H]+) 173([M+H]+) HO~- 566 567 MeO2C'~N ~N MS(ESI) m/z:
* H I NJ 226 ([M+H]+) HO, 566 02~ 577 568 Me0 C N (~ MS(FAB) m/z: 577 ~~ MS(FAB) m/z:
2 H ~N 259 ([M+H]+) O 320 ([M+H]+) TBS NHBoc O
O OH 564 Me02 577 569 ~/ `N~ MS(ESI) m/z: %N>
H CO2Me 578 ( MS EI ) m/z:
360([M+H]+} ci 238 ([M]+) OT
IO OH 564 Me02 577 570 NT MS(ESI) m/z: 579 MS(FAB) mlz:
* CO2Me 360([M+H]+) 205 ([M+H]+) 0 OH 564 Me02 577 571 N N MS(FAB) mlz: 580 ,N MS(FAB) m/z:
*, Boc CO2Me 317([M+H]+) O N 206 ([M+H]+) Boc 564 W02 577 N 0 OH 581 ~ ~ MS(ESI) m/z:
572 ~ MS(ESI) m/z:
O~N-~' O N 206 ([M+H]+) * CO2Me 333([M+H]+) TBS 02Me 577 O O OH 564 582 OMe MS(FAB) m/z:
N
573 N~ MS(ESI) m/z: 235 ([M+H]+) * CO2Me 360([M+H]+) CO2Me ~Boc 577 OH 583 N}~ MS(FAB) m/z:
'k 0 0 313([M+H]+) C02 Me 564 TBS
O~ ~N-H 577 O MS(FAB) m/z: O fO
574 Br ~ 332 M+H + 584 ~ 1 MS(ESI) m/z:
~ ([ ] ) N
\ Me0 C 340([M+H]+) ~ CO2Me 585 \c~.,.
MS(ESI) m/z:
575 O~H MS(FAB) m/z:
e ~ 192([M+H]+) MeO2C 340([M+H]+) M

Me >-o / TBS 0 577 o ~
Me OH 564 586 O~( ~~`Ni MS(ESI) m/z:
576 MS FAB m/z: v N ( ) CO2Me 340([M+H]+) * CO2Me 220([M+H]+) O 577 EtO2 596 587 N\ N CO Me MS(ESI) m/z: 597 MS(ESI) N~ (ESI) mlz:
Boc 2 297([M+H]+) O 224 ([M+H]+) Br O\ 577 EtO2C 596 588 ON MS(FAB) m/z: 598 t~ l MS(ESI) m/z:
MeO2C 311([M+H]+) O O 208 ([M+H]+) Me p O 577 EtO 2 596 589 MeN ` MS(CI) m/z: 599 \ MS(ESI) m/z:
O N
MeO2C 200([M+H]+) Boc 307 ([M+H]+) 577 CO Et 600 590 Me/O~N 1 MS(FAB) m/z: 600 MS(API) m/z:
MeO2C 172([M+H]+) 301 [M+H]+) C02fMe N 21 O N Me 601 591 ~ ~ MS(ESI) m/z: 601 N Me MS(FAB) m/z:

* 197([M+H]+ ` ) p OH
185(LM+HI+) C02Me p~Me 592 N 0 602 i 592 N N MS(ESI) m/z: 602 ~ N 4 Me MS(EI) m/z:

~
p~ , 239([M+H]+) Me 166(LMI+) Me O 593 O~
N Me 603 593 HpMS(ESI) m/z: HO N
Me02C 226([M+H]+) 603 \ MS(FAB) m/z:
O 273([M+H]+) .
594 HO N MS(ESI) m/z: OH 604 N
Me02C 226([M+H]+) 604 / 2 CO H MS(FAB) m/z:

HO~.,,~~~~ 593 220(LM+HI+) 595 N MS(ESI) m/z:
Me02C 226([M+H]+) H02C [-NCiio \ 605 605 MS(ESI) m/z:
Et02 596 O
596 MS(ESI) m/z: 197 ([M-H] ) 208 (LM+HI+) 606 tFS_KID_oH MS(ESI) m/z:
p 213 ([M+H]+) 607 N MS(ESI) m/z: 618 ~N}-~O MS(ESI) m/z:
197 ([M+H]+) 0 198([M+H]+) COZH Me 605 Co NH pH 605 608 ~~- J OMe MS(ESI) m/z: 619 ~ , MS(ESI) m/z:
~ 201 ([M+H]+) O 210([M-H]-) 609 MS(ESI) m/z: 620 ~ MS(FAB) m/z:
O 191 ([M+H]+) 0 196([M+H]+) HOZC I\ _ 605 Cp2H Boc MS(ESI) m/z: 621 N\ ~ MS(ESI) m/z:
O N 192 ([M+H]+) 0 p 297([M-H]-) HO2C 605 _ 611 MS(ESI) m/z: CO H \/ 605 MS
(ESI) m/z:
O 192 ([M+H]+) 622 \N,LII) HO 2 605 273([M+H]+) _ \ O
612 I O \~ MS(FAB) m/z: CO2H OH 605 CI 223 ([M-H]-) 623 MS(ESI) m/z:
OZH 605 LN> 210([M-H]-) 613 to MS(FAB) m/z: CO2H 605 304 ([M-H]-) 624 ~NO MS(FAB) mlz:
NHBoc 0 Br 298([M+H]+) HOzC~ ~ ~ 605 C02H Me 614 MS(ESI) mlz: 605 O 180 ([M+H]+) 625 LO MS(FAB) m/z:
H02605 186([M+H]+) 615 p MS(ESI) m/z: C02H Me 605 196 ([M+H]+) 626 O~ MS(FAB) mlz:
HO2C N 605 158([M+H]+) 616 `p p MS(FAB) m/z: + O~
180 ([M+H]+) Na ~~ Me 605 (Na) CO2H 605 627 O N=~N MS(ESI) m/z:
N}-~~OH MS(ESI) m/z: 0 O 241([M+H]*) O `~
212([M+H]+) CO 2H Me 605 628 ~ ~ N MS(ESI) m/z:
* O ~J 223([M-H]-) 629 N} C" MS(ESI) m/z:
O N
H 207 ([M+H]+) Hereinafter, the representative preparation methods are described with reference to Examples. Example 1 to Example 1202 as described in Tables 6 to 68 can be prepared in the same manner as any one of the following representative preparation methods of Examples, and Example No. corresponding to each is shown as Syn of Tables.
Example 17 To a solution of 950 mg of N-[2-(aminocarbonyl)-6-(4-methylpiperazin-l-yl)phenyl]-2-phenyl-l,3-thiazole-4-carboxamide in 10.0 ml of acetic acid was added 10.0 ml of concentrated sulfuric acid. A solution of 310 mg sodium nitrite in 3.00 ml of water was added thereto under ice-cooling, followed by stirring at room temperature for 5 hours. To the reaction liquid was added water, followed by extraction with chloroform. The organic layer was dried over magnesium sulfate, a solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=95:5) to prepare 123 mg of 3-(4-methylpiperazin-1-yl)-2-{[(2-phenyl-1,3-thiazol-4-yl)carbonyl]amino}benzoic acid.
Example 28 300 mg of 2-phenyl-N-(2-piperazin-l-ylphenyl)-1,3-thiazole-4-carboxamide and 200 l of pyridine were dissolved in 10 ml of dichloroethane, and 180 l of acetylchloride was added dropwise thereto at room temperature, followed by stirring for one day. To the reaction liquid was added an aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform, and drying over magnesium sulfate. A solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=100:1) to prepare 230 mg of N-[2-(4-acetylpiperazin-1-yl)phenyl]-2-phenyl-1,3-thiazole-4-carboxamide.

Example 29 300 mg of 2-phenyl-N-(2-piperazin-l-ylphenyl)-1,3-thiazole-4-carboxamide and 600 l of pyridine were dissolved in 10 ml of dichloroethane, and 708 l of ethyl chloroformate was added dropwise thereto at room temperature, followed by stirring at room temperature for one day. To the reaction liquid was added an aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform, and drying over magnesium sulfate. A

solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=100:1) to prepare 213 mg of 4-(2-{[(2-phenyl-1,3-thiazol-4-yl) carbonyl]amino}phenyl)-1-piperazinecarboxylic acid ethyl ester.

Example 31 300 mg of 2-phenyl-N-(2-piperazin-1-ylphenyl)-1,3-thiazole-4-carboxamide, and 600 l of pyridine were dissolved in 10 ml of dichloroethane, and 570 l of methanesulfonyl chloride was added dropwise thereto at room temperature, followed by stirring at room temperature for one day. To the reaction liquid was added an aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform and drying over magnesium sulfate. A solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=100:1) to prepare 315 mg of N-{2-[4-(methanesulfonyl)piperazin-l-yl]phenyl}-2-phenyl-l,3-thiazole-4-carboxamide.

Example 36 2.18 g of 1-(2-{[(2-phenyl-1,3-thiazol-4-yl)carbonyl]amino}phenyl)piperidine-4-carboxylic acid ethyl ester was dissolved in 100 ml of methanol, 20 ml of a 1M
aqueous sodium hydroxide solution was added dropwise thereto at room temperature, followed by stirring at 50 C
for 3 hours. To the reaction liquid was added dropwise 20 ml of a 1M aqueous hydrochloric acid solution, followed by extraction with chloroform and drying over magnesium sulfate. A solvent was evaporated under reduced pressure to prepare 1.82 g of 1-(2-{[(2-phenyl-1,3-thiazol-4-yl)carbonyl]amino}phenyl)piperidine-4-carboxylic acid.
Example 63 To a suspension of 300 mg of 1-(4-(2-amino-2-oxoethyl)-2-{(2-phenyl-1,3-thiazol-4-yl)carbonyl]amino}phenyl)piperidine-4-carboxamide in 6.00 ml of THF was added 200 mg of triethylamine, and 500 l of trifluoroacetic anhydride was added thereto at 0 C, followed by stirring at room temperature for 3 days. The reaction liquid was adsorbed on silica gel, followed by purification using column chromatography (chloroform:methanol=95:5) to prepare 239 mg of N-[5-(cyanomethyl)-2-(4-cyanopiperidin-1-yl)phenyl]-2-phenyl-1,3-thiazole-4-carboxamide.

Example 68 To a solution of 500 mg of 1-(2-aminophenyl)pyrrolidine-3-carboxylic acid methyl ester in 20 ml of DMF were added 562 mg of 2-phenyl-1,3-thiazole-4-carboxylic acid, 653 mg of WSC-HC1, and 460 mg of HOBt at room temperature, followed by stirring for 8 hours. To the reaction liquid was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform, drying over sodium sulfate, and filtration. A

solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:EtOAc=4:1) to prepare 1.169 g of 1-(2-{[(2-phenyl-1,3-thiazol-4-yl) carbonyl]amino}phenyl)pyrrolidine-3-carboxylic acid methyl ester.

Subsequently, 969 mg of this product was dissolved in 30 ml of methanol and 10 ml of THF, and 4.76 ml of a 1 M
aqueous sodium hydroxide solution was added dropwise thereto at room temperature, followed by stirring at 50 C
for one day. To the reaction liquid was added dropwise 4.76 ml of a 1 M aqueous hydrochloric acid solution, followed by extraction with chloroform and drying over magnesium sulfate. A solvent was evaporated under reduced pressure to prepare 708 mg of 1-(2-{[(2-phenyl-1,3-thiazol-4-yl)carbonyl]amino}phenyl)-3-pyrrolidinecarboxylic acid.
Example 76 To a solution of 700 mg of 2-phenyl-N-[2-(4-thiomorpholinyl)phenyl]-1,3-thiazole-4-carboxamide in 40 ml of chloroform was added 301 mg of m-chloroperbenzoic acid, followed by stirring at room temperature for 4 hours. To the reaction liquid was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform, and the organic layer was washed with saturated brine, dried over sodium sulfate, and then filtered. A

solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform), and crystallized from 9 ml of ethanol to prepare 457 mg of N-[2-(1-oxide-4-thiomorpholinyl)phenyl]-2-phenyl-l,3-thiazole-4-carboxamide.
Examples 77 and 78 To a solution of 300 mg of N-[2-(1-oxide-4-thiomorpholinyl)phenyl]-2-phenyl-1,3-thiazole-4-carboxamide in 20 ml of chloroform was added 124 mg of m-chloroperbenzoic acid, followed by stirring at room temperature for 29 hours. To the reaction liquid was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform, and the organic layer was washed with saturated brine, dried over sodium sulfate, and then filtered. A solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to prepare 104 mg of N-[2-(1,1-dioxide-4-thiomorpholinyl)phenyl]-2-phenyl-1,3-thiazole-4-carboxamide (Example 77) and 56 mg of N-[2-(1,4-dioxide-4-thiomorpholinyl)phenyl]-2-phenyl-1,3-thiazole-4-carboxamide (Example 78).

Example 85 To a suspension of 200 mg of 2-phenyl-N-[2-(4-piperidinyl)phenyl]-1,3-thiazole-4-carboxamide hydrochloride in 9 ml of DMF - 3 ml of ethanol were added 280 mg of potassium carbonate and 108 l of (2-bromoethoxy)-tert-butyldimethylsilane, followed by stirring at room temperature for 24 hours. To the reaction liquid was added 100 ml of water, followed by extraction with chloroform, and the organic layer was washed with saturated brine, dried over sodium sulfate, and then filtered. A
solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=40:1) to prepare 118 mg of N-{2-[1-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-4-piperidinyl]phenyl}-2-phenyl-1,3-thiazole-4-carboxamide.

This was suspended in 2 ml of ethanol, and 0.2 ml of a 37% aqueous hydrochloric acid solution was added thereto, followed by stirring at room temperature for 35 min. A

solvent was evaporated under reduced pressure, followed by washing with diethyl ether to prepare 49 mg of N-{2-[l-(2-hydroxyethyl)-4-piperidinyl]phenyl}-2-phenyl-1,3-thiazole-4-carboxamide hydrochloride.

Example 94 A solution of 2.19 g of (2E)-3-(2-{[(2-phenyl-1,3-thiazol-4-yl) carbonyl]amino}phenyl)acrylic acid methyl ester and 1.57 g of N-benzyl-l-methoxy-N-[(trimethylsilyl)methyl]methaneamine in 40.0 ml of toluene was warmed to 50 C. To this was added portionwise and dropwise a solution of 46.3 l of trifluoroacetic acid in 10.0 ml of toluene, followed by stirring at the same temperature for 18 hours. The reaction liquid was concentrated, and the residue was purified by silica gel column chromatography (chloroform:methanol=97:3). This was dissolved in ethanol, a 4 M hydrogen chloride/ethyl acetate solution was added thereto, and a solvent was evaporated under reduced pressure to prepare 2.35 g of trans-l-benzyl-4-(2-{[(2-phenyl-1,3-thiazol-4-yl)carbonyl]amino}phenyl)pyrrolidine-3-carboxylic acid methyl ester hydrochloride.

Example 95 To 2.35 g of trans-l-benzyl-4-(2-{[(2-phenyl-1,3-thiazol-4-yl)carbonyl]amino}phenyl)pyrrolidine-3-carboxylic acid methyl ester hydrochloride was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was dried over magnesium sulfate, and a solvent was evaporated under reduced pressure. The residue was dissolved in dichloroethane, 542 mg of 1-chloroethylchlorocarbonate was added thereto, followed by heating under reflux for 1 hour, and then the reaction liquid was evaporated under reduced pressure. Thereafter, to the residue was added methanol, followed by heating under reflux for 3 hours. The reaction liquid was concentrated, and the residue was purified by silica gel column chromatography (chloroform:methanol=92:8) to prepare 123 mg of trans-4-(2-{[(2-phenyl-l,3-thiazol-4-yl)carbonyl]amino}phenyl) pyrrolidine-3-carboxylic acid methyl ester.
Example 99 To a suspension of 170 mg of 2-phenyl-N-[2-(1,2,3,6-tetrahydro-4-pyridinyl)phenyl]-1,3-thiazole-4-carboxamide hydrochloride in 7 ml of THF was added 0.30 ml of Et3N, and then 170 l of trimethylsilylisocyanate was added thereto under ice-cooling, followed by stirring at room temperature for 8 days. To the reaction liquid was added 100 ml of water, followed by extraction with EtOAc, and the organic layer was washed with saturated brine, dried over sodium sulfate, and then filtered. A solvent was evaporated under reduced pressure, and the residue was washed with 10 ml of chloroform to prepare 172 mg of 4-(2-{[(2-phenyl-1,3-thiazol-4-yl)carbonyl]amino}phenyl)-3,6-dihydro-1(2H)-pyridinecarboxamide.

Example 100 To a suspension of 170 mg of 2-phenyl-N-[2-(1,2,3,6-tetrahydro-4-pyridinyl)phenyl]-1,3-thiazole-4-carboxamide hydrochloride in 7 ml of THF was added 0.30 ml of triethylamine, and 60 l of 4-morpholinecarbonylchloride was added thereto under ice-cooling, followed by stirring at room temperature for 2 hours. To the reaction liquid was added 100 ml of water, followed by extraction with EtOAc, and the organic layer was washed with saturated brine, dried over sodium sulfate, and then filtered. A
solvent was evaporated under reduced pressure, and the residue was recrystallized from 5 ml of ethanol to obtain 165 mg of N-{2-[1-(4-morpholinylcarbonyl)-1,2,3,6-tetrahydro-4-pyridinyl]phenyl}-2-phenyl-1,3-thiazole-4-carboxamide.

Example 119 To a solution of 414 mg of 2-(4-pyridinyl)-1,3-thiazole-4-carboxylic acid ethyl ester in 10 ml of methanol was added 2 ml of a 4 M aqueous lithium hydroxide solution, followed by stirring at room temperature for 2 hours, and then to the reaction liquid was added a 1 M aqueous hydrochloric acid solution, followed by acidification of the system. A solvent was evaporated under reduced pressure, to the residue was added 20 ml of thionyl chloride, followed by stirring overnight at 80 C, the reaction liquid was evaporated under reduced pressure, the residue was suspended in 10 ml of dichloromethane, and 329 mg of 1-(2-aminophenyl)-4-piperidinecarboxamide and 1.25 ml of triethylamine were added thereto, followed by stirring overnight at room temperature. To the reaction liquid were added a saturated aqueous sodium hydrogen carbonate solution and chloroform, the insolubles was collected by filtration, and suspended in chloroform-methanol, and then the insolubles were removed by filtration. To the obtained solution was added a 4 M hydrogen chloride/EtOAc solution, followed by evaporation under reduced pressure, and then the residue was crystallized from diethyl ether to obtain 320 mg of 1-[2-({[2-(4-pyridinyl)-1,3-thiazol-4-yl]carbonyl}amino)phenyl]-4-piperidinecarboxamide hydrochloride.

Example 130 To 125 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-l-yl]phenyl}-2-(6-methoxypyridin-3-yl)-1,3-thiazole-4-carboxamide was added dropwise 3.00 ml of a 48% hydrogen bromide solution, followed by stirring at room temperature for 25 min. The reaction liquid was concentrated under reduced pressure, and the obtained residue was washed with ethanol to prepare 123 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-1-yl]phenyl}-2-(6-oxo-1,6-dihydropyridin-3-yl)-1,3-thiazole-4-carboxamide hydrobromide.

Example 142 To 360 mg of 2-(6-hydroxy-3-pyridinyl)-1,3-thiazole-4-carboxylic acid was added 8.0 ml of phosphorus oxychloride, followed by stirring at 90 C for 8 hours. A
solvent was evaporated under reduced pressure, then the residue was suspended in 5 ml of pyridine, and 355 mg of 1-(2-aminophenyl)-4-piperidinecarboxamide was added thereto, followed by stirring overnight at room temperature. To the reaction liquid was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with EtOAc, and then the organic layer was washed a 1 M aqueous hydrochloric acid solution. A solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:EtOAc=1:0 to 1:1) to prepare 79 mg of 2-(6-chloro-3-pyridinyl)-N-[2-(4-cyano-l-piperidinyl)phenyl]-1,3-thiazole-4-carboxamide.
Example 146 To 17.1 g of 4-(2-{[(2-morpholin-4-yl-1,3-thiazol-4-yl)carbonyl]amino}phenyl)piperazine-l-carboxylic acid tert-butyl ester was added 100 ml of a 4 M hydrogen chloride/dioxane, followed by stirring at room temperature for 4 hours. The reaction liquid was concentrated, and recrystallized from methanol to prepare 8.33 g of 2-morpholin-4-yl-N-(2-piperazin-1-ylphenyl)-1,3-thiazole-4-carboxamide hydrochloride.

Example 167 To a solution of 105 mg of morpholine in 4.00 ml of DMF were added 500 mg of sodium [4-(2-{[(2-morpholin-4-yl-1,3-thiazol-4-yl)carbonyl]amino}phenyl)piperazin-l-yl]acetate, 275 mg of WSC-HC1, 194 mg of HOBt at room temperature, followed by stirring for 6 hours. To the reaction liquid was added water, the insolubles were collected by filtration, and dissolved in ethanol, a 4 M
hydrogen chloride/EtOAc solution was added thereto, and a solvent was evaporated under reduced pressure to prepare 564 mg of 2-morpholin-4-yl-N-{2-[4-(2-morpholin-4-yl-2-oxoethyl)piperazin-1-yl]phenyl}-1,3-thiazole-4-carboxamide hydrochloride.

Example 169 To a mixed solution of 400 mg of N-(2-{4-[2-(2,5-dihydro-lH-pyrrol-1-yl)-2-oxoethyl]piperazin-1-yl}phenyl)-2-morpholin-4-yl-1,3-thiazole-4-carboxamide in 4.00 ml of THF and 1.00 ml of water was added 120 mg of 4-methylmorpholine-4-oxide and 1.00 ml of a 0.08 M solution of osmium tetroxide in tert-butanol, followed by stirring at room temperature for 24 hours. A saturated aqueous sodium thiosulfate solution was added thereto, followed by extraction with EtOAc, and the organic layer was washed with saturated brine, and then dried over magnesium sulfate. A solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=95:5) . This was dissolved in ethanol, a 4 M hydrogen chloride/EtOAc solution was added thereto, and then a solvent was evaporated under reduced pressure to prepare 51.0 mg of N-(2-{4-[2-(cis-3,4-dihydroxypyrrolidin-1-yl)-2-oxoethyl]piperazin-1-yl}phenyl)-2-morpholin-4-yl-1,3-thiazole-4-carboxamide hydrochloride.

Example 185 To a solution of 300 mg of 2-morpholin-4-yl-N-(2-piperazin-1-ylphenyl)-1,3-thiazole-4-carboxamide hydrochloride in 15.0 ml of DMF were added 350 mg of potassium carbonate and 95.0 mg of 3-(chloromethyl)-1,2,4-oxadiazole, followed by stirring at room temperature for 18 hours. The reaction liquid was concentrated, and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with chloroform. The organic layer was dried over magnesium sulfate, a solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methano1=96:4). This was dissolved in ethanol, a 4 M hydrogen chloride/EtOAc solution was added thereto, and then a solvent was evaporated under reduced pressure to prepare 62.0 mg of 2-morpholin-4-yl-N-{2-[4-(1,2,4-oxadiazol-3-ylmethyl)2-piperazin-l-yl]phenyl}-1,3-thiazole-4-carboxamide hydrochloride.

Example 191 To a suspension of 600 mgof 2-morpholin-4-yl-N-(2-piperazin-l-ylphenyl)-1,3-thiazole-4-carboxamide hydrochloride in 10.0 ml of acetonitrile were added 25.0 1 of acetic acid, 293 mg of tetrahydro-4H-pyran-4-one, and 1.55 g of sodium triacetoxyborohydride, followed by stirring at room temperature for 7 days. To the reaction liquid was added a saturated aqueous sodium hydrogen carbonate solution, and the resulting insolubles were collected by filtration, and washed with acetonitrile.
This was dissolved in ethanol, a 4 M hydrogen chloride/EtOAc solution was added thereto, and then a solvent was evaporated under reduced pressure to prepare 224 mg of 2-morpholin-4-yl-N-{2-[4-(tetrahydro-2H-pyran-4-yl)piperazin-l-yl]phenyl}-1,3-thiazole-4-carboxamide hydrochloride.

Example 192 To a solution of 300 mg of 2-morpholin-4-yl-N-(2-piperazin-l-ylphenyl)-1,3-thiazole-4-carboxamide hydrochloride in 10.0 ml of dioxane were added 300 l of triethylamine and 315 mg of 3,6-dioxabicyclo[3.1.0]hexane, followed by heating under reflux for 3 days. The reaction liquid was concentrated, and the residue was purified by silica gel column chromatography (chloroform:methanol=96:4). This was dissolved in ethanol, a 4 M hydrogen chloride/EtOAc solution was added thereto, and then a solvent was evaporated under reduced pressure to prepare 38.0 mg of N-{2-[4-(trans-4-hydroxytetrahydrofuran-3-yl)piperazin-1-yl]phenyl}-2-morpholin-4-y1-1,3-thiazole-4-carboxamide hydrochloride.

Example 206 To a suspension of 204 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-1-yl]-4-bromophenyl}-2-morpholin-4-yl-1,3-thiazole-4-carboxamide and 47.0 mg of zinc cyanide in 2.00 ml of DMF was added 13.8 mg of tetrakistriphenylphosphine palladium, followed by radiation with microwave and stirring at 190 C for 30 min, and then at 200 C for 90 min. After cooling to room temperature, EtOAc and a 28% aqueous ammonia solution were added thereto, and the insolubles was filtered through celite.
The organic layer was separated and dried over magnesium sulfate, a solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=96:4) . This was dissolved in ethanol, a 4 M hydrogen chloride/EtOAc solution was added thereto, and then a solvent was evaporated under reduced pressure to prepare 108 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-1-yl]-4-cyanophenyl}-2-morpholin-4-yl-1,3-thiazole-4-carboxamide hydrochloride.
Example 234 455 mg of 2-(morpholin-4-yl)-1,3-thiazole-4-carboxylic acid and a catalytic amount of 16 l of DMF were dissolved in 20 ml of dichloroethane, and 740 l of oxalylchloride was added dropwise thereto, followed by stirring at room temperature for 30 min. A solvent was evaporated under reduced pressure, and the residue was added dropwise to a solution of 316 mg of 1-(3-aminopiperazin-2-yl)-4-(hydroxymethyl)-4-piperidinol and 789 l of triethylamine in 20 ml of tetrahydrofuran, followed by stirring at room temperature for 15 min. To the reaction liquid was added an aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform and drying over magnesium sulfate. A solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=50:1 to 10:1) This was suspended in EtOAc, a 4 M hydrogen chloride/EtOAc solution was added thereto, and then a solvent was evaporated under reduced pressure to prepare 555 mg of N-{2-[4-hydroxy-4-(hydroxymethyl)piperazin-1-yl]pyridin-3-yl}-2-(morpholin-4-yl)-1,3-thiazole-4-carboxamide hydrochloride.
Example 266 To a solution of 220 mg of 1-(4-fluoro-2-{[(2-morpholin-4-yl-1,3-thiazol-4-yl)carbonyl]amino}phenyl)piperidine-4-carboxylic acid and 59 mg of methanesulfonamide in 8 ml of DMF were added 120 mg of WSC-HC1 and 13 mg of 4-dimethylaminopyridine, followed by stirring at room temperature for 17 hours.

To the reaction liquid was added water, followed by extraction with EtOAc, and the organic layer was washed with a 10% citric acid solution and then with saturated brine, and dried over sodium sulfate. A solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methano1=100:1). This was recrystallized from 15 ml of methanol to obtain 68 mg of 1-(4-fluoro-2-{[(2-morpholin-4-yl-1,3-thiazol-4-yl)carbonyl]amino}phenyl)-N-(methylsulfonyl)piperidine-4-carboxamide.
Example 267 To a solution of 247 mg of 1-(6-fluoro-3-{[(2-morpholin-4-yl-1,3-thiazol-4-yl)carbonyl]amino}pyridin-2-yl)-4-hydroxypiperidine-4-carboxylic acid in 8.50 ml of THF
was added 500 mg of CDI, followed by stirring at room temperature for 12 hours, and then at 60 C for 3 hours.
Thereafter, a solution of 165 mg of sodium borohydride in 3.40 ml of water was added dropwise thereto under ice-cooling, followed by stirring at room temperature for 4 hours. The reaction liquid was concentrated, and to the residue was added water, followed by extraction with EtOAc.

The organic layer was dried over magnesium sulfate, a solvent was evaporated under reduced pressure, and the residue was recrystallized from ethanol to prepare 132 mg of N-{6-fluoro-2-[4-hydroxy-4-(hydroxymethyl)piperidin-l-y1]pyridin-3-yl}-2-morpholin-4-yl-1,3-thiazole-4-carboxamide.

Example 281 To a solution of 195 mg of 1-(5-bromo-3-{[(2-morpholin-4-yl-1,3-thiazol-4-yl)carbonyl]amino}pyridin-2-yl)piperidine-4-carboxamide in 1.95 ml of DMF were added 33.0 mg of sodium acetate, 50 l of acrylonitrile, 9.0 mg of tri-o-tolylphosphine, and 9.0 mg of palladium acetate, followed by radiation with microwave and stirring at 200 C
for 10 min. To the reaction liquid was added water, followed by extraction with EtOAc, and the organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate, a solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=96:4) to prepare 85.2 mg of 1-(5-[(E)-2-cyanovinyl]-3-{[(2-morpholin-4-y1-1,3-thiazol-4-yl)carbonyl]amino}pyridin-2-yl)piperidine-4-carboxamide.
Example 287 To a mixed solution of 71.0 mg of 1-(5-[(E)-2-cyanovinyl]-3-{[(2-morpholin-4-yl-1,3-thiazol-4-yl)carbonyl]amino}pyridin-2-yl)piperidine-4-carboxamide in 2.0 ml of methanol and 2.0 ml of THF was added 10.0 mg of 10% palladium/carbon, followed by stirring under a hydrogen atmosphere for 15 hours. The reaction liquid was filtered through celite, the mother liquor was concentrated, and the residue was recrystallized from ethanol to prepare 51.3 mg of 1-(5-[-2-cyanoethyl]-3-{[(2-morpholin-4-yl-1,3-thiazol-4-yl)carbonyl]amino}pyridin-2-yl)piperidine-4-carboxamide.
Example 288 To a suspension of 500 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-1-yl]-5-bromophenyl}-2-morpholin-4-yl-1,3-thiazole-4-carboxamide in 3.00 ml of propanol were added 40.0 mg of [1,1'-bis(diphenylphosphino)ferrocene]-dichloropalladium (II), 400 mg of potassium vinyltrifluoroborate and 0.15 ml of triethylamine, followed by radiation with microwave and stirring at 120 C for 15 min. The precipitate was separated by filtration, and washed with ethanol, and the mother liquor was concentrated under reduced pressure. The obtained residue was diluted in 30 ml of saturated brine, and extracted with chloroform.
The organic layer was dried over sodium sulfate, and then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=96:4) to prepare 360 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-1-yl]-5-vinylphenyl}-2-morpholin-4-yl-1,3-thiazole-4-carboxamide.
Example 293 To a solution of 200 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-1-yl]-5-bromophenyl}-2-morpholin-4-yl-1,3-thiazole-4-carboxamide in 1.00 ml of DMF were added 14.0 mg of dichlorobis(triphenylphosphine)palladium (II) and 200 mg of tributyl(methoxymethyl)tin, followed by radiation with microwave and heating at 200 C for 15 min.

To the reaction liquid were added EtOAc and a saturated aqueous potassium fluoride solution, followed by stirring for a while. The organic layer was separated, dried over sodium sulfate, and then concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=95:5) to prepare 16.2 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-l-yl]-5-(methoxymethyl)phenyl}-2-morpholin-4-yl-1,3-thiazole-4-carboxamide.

Example 356 300 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-l-yl]phenyl}-2-bromo-l,3-thiazole-4-carboxamide was dissolved in 20 ml of dioxane, and 380 l of (2-methoxyethyl)methylamine was added dropwise thereto at room temperature, followed by stirring at 100 C for 3 days. To the reaction liquid was added an aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform and drying over magnesium sulfate. A solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methano1=50:1). After this was suspended in EtOAc, a 4 M hydrogen chloride/EtOAc solution was added thereto, and then a solvent was evaporated under reduced pressure to prepare 206 mg of N-{2-[4-(2-amino-2-oxoethyl)-piperazin-1-yl]phenyl}-2-[(2-methoxyethyl)(methyl)amino]-1,3-thiazole-4-carboxamide hydrochloride.

Example 394 To a solution of 200 mg of 1-(3-aminopyridin-2-yl)-4-(hydroxymethyl)piperidin-4-ol in 10 ml of DMF were added 453 mg of 2-[(2-methoxyethyl)(methyl)amino]-1,3-thiazole-4-carboxylic acid hydrochloride, 515 mg of WSC-HC1, 363 mg of HOBt, and 0.50 ml of triethylamine, followed by stirring at room temperature for one day. Thereafter, 4.00 ml of methanol and 4.00 ml of a 4 M aqueous sodium hydroxide solution were added thereto, followed by stirring at room temperature for 1 hour. To the reaction liquid was added water, followed by extraction with chloroform, drying over magnesium sulfate, and filtration. A solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=50:1) to prepare 210 mg of N-{2-[4-hydroxy-4-(hydroxymethyl)piperidin-l-yl]pyridin-3-yl}-2-[(2-methoxyethyl)(methyl)amino]-1,3-thiazole-4-carboxamide hydrochloride.

Example 501 To a solution of 119 mg of 2-morpholin-4-yl-1,3-oxazole-4-carboxylic acid in 6.00 ml of DMF were added 132 mg of 1-(3-aminopyridin-2-yl)piperidine-4-carboxamide, 150 mg of WSC-HC1, and 105 mg of HOBt, followed by stirring at room temperature for 3 days. The reaction liquid was concentrated under reduced pressure, and an aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with chloroform. The organic layer was washed with saturated brine, and then dried over magnesium sulfate. A solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=50:1), and further recrystallized from acetonitrile. This was suspended in EtOAc, a 4 M hydrogen chloride/EtOAc solution was added thereto, and then a solid was collected by filtration to prepare 95 mg of 1-(3-{[(2-morpholin-4-yl-1,3-oxazol-4-yl)carbonyl]amino}pyridin-2-yl)piperidine-4-carboxamide hydrochloride.

Example 529 To a solution of 230 mg of 2-morpholin-4-yl-1,3-oxazole-4-carboxylic acid and 200 mg of 2-[4-(2-amino-5-bromo-4-fluorophenyl)piperazin-1-yl]acetoamide in 1.00 ml of pyridine was added 0.61 ml of phosphorus oxychloride at -20 C, followed by stirring at room temperature for 15 hours. To the reaction liquid was added water, followed by extraction with EtOAc, drying over sodium sulfate, and concentration under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=95:5) to prepare 180 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-l-yl]-4-bromo-5-fluorophenyl}-2-morpholin-4-yl-1,3-oxazole-4-carboxamide.

Example 537 To a solution of 150 mg of N-{5-[4-(2-amino-2-oxoethyl)piperazin-1-yl]-3-bromo-l-methyl-lH-pyrazol-4-yl}-2-morpholin-4-yl-1,3-oxazole-4-carboxamide in 8.00 ml methanol was.added 20.0 mg of 10% palladium-carbon, followed by stirring for 15 hours under a hydrogen atmosphere. The reaction liquid was filtered through celite, the mother liquor was concentrated, and the residue was recrystallized from ethanol to prepare 85.0 mg of N-{5-[4-(2-amino-2-oxoethyl)piperazin-l-yl]-1-methyl-lH-pyrazol-4-yl}-2-morpholin-4-yl-1,3-oxazole-4-carboxamide.

Example 635 Under an argon atmosphere, a solution of 820 mg of 2-(3-bromophenyl)-N-[2-(4-methyl-l-piperazinyl)phenyl]-1,3-thiazole-4-carboxamide in 10 ml of THF was cooled to -78 C, and 2.6 ml of a 1.5 M n-butyllithium-hexane solution was added thereto, followed by stirring for 30 min.
Subsequently, to the reaction liquid was added dry ice, followed by elevating the temperature to room temperature and stirring for 3 hours, and then water, a 1 M aqueous hydrochloric acid solution, and water were added thereto in this order to obtain a precipitate, which was collected by filtration. This was purified by silica gel column chromatography (chloroform:methanol=:100:0 to 90:10), and then dissolved in chloroform, and a 4 M hydrogen chloridelEtOAc solution was added thereto. A solvent was evaporated under reduced pressure, and then washed with diethyl ether to prepare 170 mg of 2-[4-({[2-(4-methyl-l-piperazinyl)phenyl]amino}carbonyl)-1,3-thiazol-2-yl]benzoic acid hydrochloride.

Example 662 To a solution of 480 mg of 2-(3-furyl)-1,3-thiazole-4-carboxylic acid ethyl ester in 10 ml of methanol was added 1.61 ml of a 4 M aqueous lithium hydroxide solution, followed by stirring at room temperature for 3 hours, and then to the reaction liquid was added a 1 M aqueous hydrochloric acid solution for acidification of the system.
A solvent was evaporated under reduced pressure, the residue was suspended in 10 ml of DMF, and 471 mg of 1-(2-aminophenyl)-4-piperidinecarboxamide, 348 mg of HOBt, 493 mg of WSC=HC1, and 0.90 ml of triethylamine were added thereto, followed by stirring overnight at room temperature. To the reaction liquid was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with EtOAc, and then the organic layer was washed with a 1 M aqueous hydrochloric acid solution, and saturated brine in this order. A solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 93:7) to prepare 315 mg of 1-[2-({[2-(3-furyl)-1,3-thiazol-4-yl]carbonyl}amino)phenyl]-4-piperidine carboxamide.

Example 664 To a solution of 290 mg of 1-(2-{[(2-pyrrolidin-l-yl-1,3-thiazol-4-yl)carbonyl]amino}phenyl)piperidine-4-carboxylic acid in 9.00 ml of THF was added 350 mg of CDI, followed by stirring at 50 C for 30 min. The reaction liquid was returned to room temperature, and 500 l of 28%
aqueous ammonia was added thereto, followed by continuously stirring at the same temperature for 1.5 hours. The reaction liquid was concentrated under reduced pressure, water was added thereto, and then the precipitated white solid was collected by filtration to prepare 264 mg of 1-(2-{[(2-pyrrolidin-1-yl-1,3-thiazol-4-yl)carbonyl]amino}phenyl}piperidine-4-carboxamide.
Example 691 To a solution of 90.4 mg of N-{2-[4-(2-amino-2-oxoethyl)-1-piperazinyl]phenyl}-2-(2-methoxy-4-pyridinyl)-1,3-thiazole-4-carboxamide in 2.5 ml of chloroform was added a 4 M hydrogen chloride/EtOAc solution. The precipitate was collected by filtration, and dried under reduced pressure to prepare 66.9 mg of N-{2-[4-(2-amino-2-oxoethyl)-1-piperazinyl]phenyl}-2-(2-methoxy-4-pyridinyl)-1,3-thiazole-4-carboxamide hydrochloride.

To a solution of 74.8 mg of N-{2-[4-(2-amino-2-oxoethyl)-1-piperazinyl]phenyl}-2-(2-methoxy-4-pyridinyl)-1,3-thiazole-4-carboxamide hydrochloride in 2 ml of dichloromethane was added 0.57 ml of a 1 M tribromoborane dichloromethane solution, followed by stirring overnight at room temperature. To the obtained mixture were further added 2 ml of dichloromethane and a 0.57 ml of 1 M
tribromoborane dichloromethane solution, followed by stirring overnight at room temperature. To the mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by preparative TLC, and then a 4 M hydrogen chloride/EtOAc solution in EtOAc was added thereto. The solution was concentrated and dried to prepare 25.3 mg of N-{2-[4-(2-amino-2-oxoethyl)-1-piperazinyl]phenyl}-2-(2-hydroxy-4-pyridinyl)-1,3-thiazole-4-carboxamide hydrochloride.

Example 692 To a solution of 317 mg of N-{2-[4-(2-amino-2-oxoethyl)-l-piperazinyl]phenyl}-2-(2-chloro-4-pyridinyl)-1,3-thiazole-4-carboxamide in 2.0 ml of DMSO was added 375 mg of sodium methoxide, followed by stirring at 140 C for 14 hours. The mixture was concentrated under reduced pressure, and dried, and to the mixture were added chloroform and water, followed by stirring and separation.
The aqueous layer was extracted with chloroform, and the combined organic layer was dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by HPLC, and then 5.5 ml of EtOAc and 7.5 ml of hexane were added thereto. The mixture was heated to 60 C, filtered at room temperature, and dried under reduced pressure to prepare 143.6 mg of N-{2-[4-(2-amino-2-oxoethyl)-1-piperazinyl]phenyl}-2-(2-methoxy-4-pyridinyl)-1,3-thiazole-4-carboxamide.

Example 693 To a solution of 151 mg of N-{2-[4-(2-amino-2-oxoethyl)-1-piperazinyl]phenyl}-2-(2-chloro-4-pyridinyl)-1,3-thiazole-4-carboxamide in 1.5 ml of DMSO was added 86 mg of sodium azide, and the mixture was stirred at 90 C for 2 hours, and then at 120 C for 24 hours. To the obtained mixture was added water, followed by stirring for a while, and then the precipitate was filtered and dried. To the obtained powder was added methanol, followed by stirring at 80 C for 1 hour, filtration, and drying at room temperature to prepare 44 mg of N-{2-[4-(2-amino-2-oxoethyl)-1-piperazinyl]phenyl}-2-(2-azide-4-pyridinyl)-1,3-thiazole-4-carboxamide.

To a solution of 53 mg of N-{2-[4-(2-amino-2-oxoethyl)-1-piperazinyl]phenyl}-2-(2-azide-4-pyridinyl)-1,3-thiazole-4-carboxamide in 15.9 ml of methanol and 5.3 ml of THF was added 78 mg of 10% palladium-carbon, and a 4 M hydrogen chloride/EtOAc solution was added thereto, followed by stirring overnight at room temperature under a hydrogen atmosphere. The mixture was filtered, and the filtrate was concentrated under reduced pressure. To a solution of the residue in chloroform and methanol was added a saturated aqueous sodium hydrogen carbonate solution, concentrated under reduced pressure, and dried.

The residue was thoroughly washed with a mixed solvent of methanol and chloroform (10:90), and the washing liquid was concentrated under reduced pressure. The residue was purified by preparative TLC, and a 4 M hydrogen chloride/EtOAc solution in a mixed solution of methanol and chloroform was added thereto, followed by concentration under reduced pressure. The residue was washed with a mixed solvent of methanol and isopropyl ether to prepare 24 mg of N-{2-[4-(2-amino-2-oxoethyl)-1-piperazinyl]phenyl}-2-(2-amino-4-pyridinyl)-1,3-thiazole-4-carboxamide dihydrochloride.

Example 695 A solution of 100 mg of N-{2-[4-(2-amino-2-oxoethyl)-1-piperazinyl]phenyl}-2-(2-chloro-4-pyridinyl)-l,3-thiazole-4-carboxamide, 350 mg of dimethylamine hydrochloride, and 0.61 ml of triethylamine in 1.2 ml of DMSO was stirred overnight at 140 C. To the mixture was added water, followed by extraction with chloroform. The extract solution was washed with saturated brine, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified using preparative TLC, a 4 M hydrogen chloride/EtOAc solution in a mixed solution of methanol and chloroform was added thereto, and then the solution was concentrated. The residue was washed with a mixed solvent of methanol and isopropyl ether, and dried under reduced pressure to prepare 47.7 mg of N-{2-[4-(2-amino-2-oxoethyl)-l-piperazinyl]phenyl}-2-(2-(dimethylamino)-4-pyridinyl)-1,3-thiazole-4-carboxamide dihydrochloride.

Example 698 To a solution of 46 mg of N-{2-[4-(2-amino-2-oxoethyl)-1-piperazinyl]phenyl}-2-(2-cyano-4-pyridinyl)-1,3-thiazole-4-carboxamide in 1 ml of DMSO were added 71 mg of powdered potassium carbonate and 0.015 ml of 30% aqueous hydrogen peroxide at 0 C. The mixture was stirred at room temperature for 1.5 hours, and then at 120 C for 24 hours, to the mixture was added water, and then the precipitate was collected, filtered, and then dried. To the residue was added a 4 M hydrogen chloride/EtOAc solution in a mixed solution of methanol and chloroform, and the solution was concentrated. The residue was washed with a mixed solvent of methanol and isopropyl ether to prepare 44 mg of 4-{4-[({2-([4-(2-amino-2-oxoethyl)-1-piperazinyl]phenyl}amino)carbonyl]-1,3-thiazol-2-yl}-2-pyridinecarboxamide hydrochloride.

Example 703 A solution of 203.6 mg of N-{2-[4-(2-amino-2-oxoethyl)-l-piperazinyl]phenyl}-2-bromo-1,3-thiazole-4-carboxamide and 687.1 mg of 1,4-dioxa-8-azaspiro[4.5]decane in 1.02 ml of DMA was stirred overnight at 100 C, and then the mixture was concentrated and dried under reduced pressure. To the residue was added 30 ml of water, and stirred at room temperature for 2 hours. The precipitate was collected by filtration, dried under reduced pressure at 50 C, and purified by preparative TLC to obtain 200 mg of a solid. To a solution of the resulting product in 30 ml of acetone was added 228 mg of p-toluenesulfonic acid hydrate. The mixture was stirred at room temperature for 4 hours, and then at 40 C for 3 days, and then to the mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by preparative TLC, and dissolved in a mixed solution of methanol and chloroform, and a 4 M hydrogen chloride/EtOAc solution was added thereto.. The solution was concentrated, and the residue was washed with a mixed solvent of ethanol and isopropyl ether, and dried under reduced pressure to prepare 170.6 mg of N-{2-[4-(2-amino-2-oxomethyl)-l-piperazinyl]phenyl}-2-(4-oxo-l-piperidinyl)-1,3-thiazole-4-carboxamide hydrochloride.

Examples 718 and 734 A solution of 151 mg of N-{2-[4-(2-amino-2-oxoethyl)-1-piperazinyl]phenyl}-2-bromo-l,3-thiazole-4-carboxamide, 333 mg of azetidine hydrochloride, and 0.5 ml of triethylamine in 1.02 ml of DMA was stirred overnight at 100 C, and then the mixture was concentrated and dried under reduced pressure. To the residue was added 30 ml of water, and then the aqueous layer was extracted with chloroform. The organic layer was dried over magnesium sulfate, and concentrated. The residue was purified using preparative TLC, and then a 4 M hydrogen chloride/EtOAc solution in a mixed solution of methanol and chloroform was added thereto. The solution was concentrated, and the obtained residue was washed with mixed solvent of ethanol and isopropyl ether, and dried under reduced pressure to obtain a mixture of two kinds of compounds. To this was added a saturated aqueous sodium hydrogen carbonate solution for neutralization, and then extracted with chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate, concentrated, and isolated using preparative TLC.

The upper fraction was washed with a mixed solvent of ethanol and isopropyl ether to prepare 17.2 mg of N-{2-[4-(2-amino-2-oxoethyl)-1-piperazinyl]phenyl}-2-(1-azetidinyl)-1,3-thiazole-4-carboxamide.

The lower fraction was dissolved in ethyl acetate, and a 4 M hydrogen chloride/EtOAc solution was allowed to act thereon, followed by washing with a mixed solvent of ethanol and isopropyl ether to prepare 82.3 mg of N-{2-[4-(2-amino-2-oxoethyl)-1-piperazinyl]phenyl}-2-[(3-chloropropyl)amino]-1,3-thiazole-4-carboxamide hydrochloride.

Example 723 To a solution of 296 mg of 2-(1-oxidethiomorpholin-4-yl)-1,3-thiazole-4-carboxylic acid in 10.0 ml of THF was added 260 l of 4-methylmorpholine and 170 l of isobutylchloridecarbonate under ice-cooling at 0 C for 5 min, followed by warming to room temperature, and stirring for 15 min. The reaction liquid was ice cooled again, and a solution of 281 mg of 2-[4-(2-aminophenyl)piperazin-l-yl]acetoamide in 8.00 ml of THF was added dropwise thereto, followed by stirring at 0 C for 1 hour, and then warmed at room temperature, followed by stirring for 8 hours. To the reaction liquid was added an aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform.
At this time, the insolubles partiti.oned between the aqueous layer and the organic layer were separated by filtration. The organic layer was washed with saturated brine, and then dried over magnesium sulfate. A solvent was evaporated under reduced pressure, the residue was mixed with the above-described insolubles, and this was subject to a recrystallization operation using ethanol to precipitate a solid, which was collected by filtration.

This was suspended in ethanol, a 4 M hydrogen chloride/EtOAc solution was added thereto, and the solid was collected by filtration to prepare 281 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-1-yl]phenyl}-2-(l-oxidothiomorpholin-4-yl)-1,3-thiazole-4-carboxamide hydrochloride.

Example 792 269 mg of 2-methoxyethanol was dissolved in 6 ml of DMF, and 141 mg of 60% sodium hydride was added thereto under ice-cooling, followed by stirring for 30 min. A
solution of 300 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-1-yl]phenyl}-2-bromo-1,3-thiazole-4-carboxamide in DMF was added thereto, followed by stirring at 60 C for 30 min. To the reaction liquid was added an aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=50:1). This was dissolved in ethanol, a 4 M hydrogen chloride/EtOAc solution was added thereto, and then the precipitated solid was collected by filtration to prepare 137 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-1-yl]phenyl}-2-(2-methoxyethoxy)-1,3-thiazole-4-carboxamide hydrochloride.

Example 793 155 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-l-yl]phenyl}-2-piperazin-1-yl-1,3-thiazole-4-carboxamide and 26 l of propionaldehyde were suspended in 2 ml of methylene chloride, and 62 l of acetic acid was added thereto, followed by stirring at room temperature for 1 hour. 76 mg of sodium triacetoxyborohydride was added thereto, followed by further stirring for 15 min. To the reaction liquid was added an aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). This was dissolved in ethanol, a 4 M hydrogen chloride/EtOAc solution was added thereto, and then the precipitated solid was collected by filtration to prepare 96 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-1-yl]phenyl}-2-(4-propylpiperazin-1-yl)-1,3-thiazole-4-carboxamide hydrochloride.

Example 815 28 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-l-yl]phenyl}-2-[(3S)-4-benzyl-3-(methoxymethyl)piperazin-l-yl]-1,3-thiazole-4-carboxamide was dissolved in 1 ml of methanol, and 28 mg of 10% palladium-carbon and 57 l of formic acid were added thereto, followed by stirring at room temperature for 7 hours. The reaction liquid was filtered through celite, and the mother liquor was evaporated under reduced pressure. To the residue was added an aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform:2-propanol=3:1, and the solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (chloroform:methanol=300:1). This was dissolved in ethanol, a 4 M hydrogen chloride/EtOAc solution was added thereto, and then the precipitated solid was collected by filtration to prepare 7 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-1-yl]phenyl}-2-[(3S)-3-(methoxymethyl)piperazin-l-y1]-1,3-thiazole-4-carboxamide hydrochloride.

Example 821 A solution of 100 mg of N-{2-[4-(2-amino-2-oxoethyl)-1-piperazinyl]phenyl}-2-bromo-1,3-thiazole-4-carboxamide and 180 mg of 3-(methoxymethyl)azetidine in 2 ml of DMA was stirred at 100 C for 48 hours, to the mixture was added water, and then the aqueous layer was extracted with chloroform. The organic layer was washed with saturated brine, and then dried over sodium sulfate. After filtration and concentration, the residue was purified by silica gel column chromatography (chloroform:methanol=99:1 to 20:1), the obtained residue was dissolved in methanol, diethyl ether was added thereto, and the precipitated solid was collected by filtration, and dried under reduced pressure to prepare 55 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-l-y1]phenyl}-2-{[3-methoxy-2-(methoxymethyl)propyl]amino}-1,3-thiazole-4-carboxamide.
Example 835 A solution of 370 mg of N-{2-[4-(2-amino-2-oxoethyl)-1-piperazinyl]phenyl}-2-bromo-1,3-thiazole-4-carboxamide, 524 mg of 3-(methylamino)pyrrolidine-l-carboxylic acid tert-butyl ester, and 0.76 ml of ethyldiisopropylamine in 1.85 ml of DMA was stirred overnight at 100 C. To the reaction liquid was added 200 ml of water, followed by extraction with chloroform. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, concentrated under reduced pressure, and purified by preparative TLC to obtain an oily substance. To a solution of this oily substance in 2 ml of methanol was added 8 ml of a 4 M aqueous hydrogen chloride/dioxane solution for reaction overnight at room temperature, and a saturated aqueous sodium hydrogen carbonate solution was added thereto, followed by extraction with chloroform. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by preparative TLC to obtain an oily substance. To a solution of this oily substance in 0.33 ml of methanol was added 3.3 ml of aqueous ammonia for overnight reaction. The obtained mixture was concentrated under reduced pressure, and purified by preparative TLC, and then a 4 M hydrogen chloride/EtOAc solution was added thereto to prepare 135 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-l-yl]phenyl}-2-[methyl(pyrrolidin-3-yl)amino]-1,3-thiazole-4-carboxamide dihydrochloride.

Example 837 To a solution of 50 mg of N-{2-[4-(2-amino-2-oxoethyl)-l-piperazinyl]phenyl}-2-bromo-l,3-thiazole-4-carboxamide, 47.2 mg of 3-(methylamino)pyrrolidine-l-carboxylic acid tert-butyl ester, and 0.041 ml of ethyldiisopropylamine in 0.5 ml of 1-methyl-2-pyrrolidone was radiated with microwave at 200 C for 30 min. To the mixture was added 100 ml of water, followed by extraction with chloroform, and the organic layer was dried over magnesium sulfate, and concentrated under reduced pressure.

The residue was purified using preparative TLC, and a 4 M
hydrogen chloride/EtOAc solution was added thereto to prepare 18.4 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-l-yl]phenyl}-2-[3-(methylamino)pyrrolidin-l-yl]-1,3-thiazole-4-carboxamide dihydrochloride.

Example 850 A solution of 147 mg of N-{2-[4-(2-amino-2-oxoethyl)-1-piperazinyl]phenyl}-2-(2-chloro-4-pyridinyl)-1,3-thiazole-4-carboxamide, 434 mg of methylamine hydrochloride, and 0.9 ml of triethylamine in 2 ml of DMSO
was radiated with microwave at 200 C for 70 min. To the obtained mixture was added water, followed by extraction with chloroform. The organic layer was combined, washed with water and saturated brine in this order, dried over magnesium sulfate, and concentrated under reduced pressure.
The residue was purified using preparative TLC, and a 4 M
hydrogen chloride/EtOAc solution was added thereto to prepare 32.1 mg of N-{2-[4-(2-(methylamino)-2-oxoethyl)-1-piperazinyl]phenyl}-2-[2-(methylamino)-4-pyridinyl]-1,3-thiazole-4-carboxamide hydrochloride.
Example 864 To a solution of 84 mg of 2-[1-(tert-butoxycarbonyl)-1H-pyrrol-2-yl]-1,3-oxazole-4-carboxylic acid ethyl ester in 2.1 ml of ethanol was added 0.17 ml of a 4 M aqueous lithium hydroxide solution, followed by stirring at room temperature for 3 hours. To the mixture was added 0.68 ml of a 1 M aqueous hydrochloric acid solution, followed by adjustment of its pH to 5 to 6 with a 1 M aqueous sodium hydroxide solution, and then concentration under reduced pressure. A solution of the concentrated residue, 64.25 mg of 2-[4-(2-aminophenyl)-1-piperazinyl]acetoamide, 236.7 mg of WSC-HC1, and 166.7 mg of HOBt in 2.52 ml of DMF was stirred overnight at room temperature. To the mixture was added 30 ml of a solution of a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with EtOAc. The organic layer was saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure.
The residue was purified by preparative TLC to prepare 32 mg of N-{2-[4-(2-amino-2-oxomethyl)-l-piperazinyl]phenyl}-2-(1H-pyrrolo-2-yl)-1,3-oxazole-4-carboxamide.
Example 952 To a solution of 120 mg of sodium 2-(4-ethoxypiperidin-1-yl)-1,3-oxazole-4-carboxylate in 3 ml of DMF were added 209 mg of 0-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate and 104 mg of 1-(3-aminopyridin-2-yl)piperidine-4-carboxamide, followed by stirring at room temperature for 3 days. Water was added thereto, and the precipitated solid was washed with water and then collected by filtration, followed by dryness to prepare 48 mg of 1-[3-({[2-(4-ethoxypiperidin-l-yl)-1,3-oxazol-4-yl]carbonyl}amino)pyridin-2-yl]piperidine-4-carboxamide.

Example 980 To a solution of 4.4 mg of 2-piperidin-1-ylaniline, 5.1 mg of 2-phenyl-l,3-thiazole-4-carboxylic acid, and 3.4 mg of HOBt in 1.00 ml of N,N-dimethylformamide were added 100 mg of PS-Carbodiimide (Argonaut Technologies, Inc.) at room temperature, followed by stirring overnight. To the reaction liquid was added 50 mg of MP-Carbonate (Argonaut Technologies, Inc.) and 50 mg of PS-Isocyanate (Argonaut Technologies, Inc.) at room temperature, followed by stirring for 4 hours, the insolubles were filtered, and the filtrate was concentrated under reduced pressure to prepare 7.3 mg of 2-phenyl-N-(2-piperidin-l-ylphenyl)-1,3-thiazole-4-carboxamide. In the same manner as in Example 980, the compounds of Examples 978 to 1000 and Examples 1092 to 1112 were prepared using the corresponding substituted aniline and carboxylic acid as starting materials.
Example 1029 To a solution of 14.1 mg of 1-fluoro-2-nitrobenzene in 100 l of acetonitrile was added a solution of 21.91 mg of 4-(piperazin-l-ylcarbonyl)morpholine in 220 l of 1-methylpyrrolidin-2-one at room temperature, followed by stirring at 80 C for 4 hours. To the reaction liquid were added 700 l of N,N-dimethylformamide and 100 mg of PS-Isocyanate (Argonaut Technologies, Inc.) at room temperature, followed by stirring overnight, the insolubles were filtered, the filtrate was concentrated under reduced pressure, and to the obtained residue was added a solution of 112.8 mg of tin chloride (II) dihydrate in 500 l of ethanol and 50 l of concentrated hydrochloric acid, followed by stirring at 70 C for 4 hours. The reaction liquid was concentrated under reduced pressure, and 1.5 ml of a 2 M aqueous sodium hydroxide solution was added thereto, followed by extraction with chloroform. A solvent was evaporated under reduced pressure, and to the residue was added a solution of 10.3 mg of 2-phenyl-1,3-thiazole-4-carboxylic acid and 6.8 mg of HOBt in 1.00 ml of N,N-dimethylformamide, and 75 mg of PL-DCC Resin (Polymer Laboratories Ltd.) at room temperature, followed by stirring overnight. To the reaction liquid were added 50 mg of MP-Carbonate (Argonaut Technologies, Inc.) and 50 mg of PS-Isocyanate (Argonaut Technologies, Inc.) at room temperature, followed by stirring overnight, the insolubles were filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by preparative high performance liquid chromatography (methanol-0.1o aqueous formic acid solution) to prepare 3.0 mg of N-{2-[4-(morpholin-4-ylcarbonyl)piperazin-l-yl]phenyl}-2-phenyl-l,3-thiazole-4-carboxamide.

From 1-fluoro-2-nitrobenzene, 2-phenyl-l,3-thiazole-4-carboxylic acid, and each corresponding starting material, in the same manner as in Example 1029, the compounds of Examples 1001 to 1044 were prepared.

Example 1048 To a solution of 7.4 mg of 1-(2-aminophenyl)piperidine-4-carboxylic acid ethyl ester, 7.4 mg of 2-(2-thienyl)-1,3-thiazole-4-carboxylic acid, and 4.1 mg of HOBt in 1.00 ml of N,N-dimethylformamide solution was added 100 mg of PS-Carbodiimide (Argonaut Technologies, Inc.) at room temperature, followed by stirring overnight.
To the reaction liquid were added 50 mg of MP-Carbonate (Argonaut Technologies, Inc.) and 50 mg of PS-Isocyanate (Argonaut Technologies, Inc.) at room temperature, followed by stirring for 4 hours, and the insolubles were filtered.
The filtrate was concentrated under reduced pressure, the obtained residue was dissolved in 0.5 ml of ethanol and 0.5 ml of tetrahydrofuran, and 0.5 ml of a 2 M aqueous sodium hydroxide solution was added dropwise thereto at room temperature, followed by stirring at 60 C for one day. To the reaction liquid was added dropwise 1.0 ml of a 1M

aqueous hydrochloric acid solution, followed by extraction with chloroform. A solvent was evaporated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (methanol-O.1o aqueous formic acid solution) to prepare 2.4 mg of 1-[2-({[2-(2-thienyl)-1,3-thiazol-4-yl]carbonyl}amino)phenyl]piperidine-4-carboxylic acid.

From 1-(2-aminophenyl)piperidine-4-carboxylic acid ethyl ester and each corresponding starting material, in the same manner as in Example 1048, the compounds of Examples 1045 to 1052 were prepared.
Example 1065 To a solution of 10.9 mg of 2-phenyl-N-(2-piperidin-4-ylphenyl)-1,3-thiazole-4-carboxamide in 0.5 ml of N,N-dimethylformamide were added 4.0 mg of 3-bromopropanenitrile and 12.4 mg of potassium carbonate, followed by stirring overnight at 60 C. To the reaction liquid was added water, followed by extraction with chloroform. A solvent was evaporated under reduced pressure, and the residue was purified by preparative high performance liquid chromatography (methanol-0.1o aqueous formic acid solution) to prepare 3.6 mg of N-{2-[1-(2-cyanoethyl)piperidin-4-yl]phenyl}-2-phenyl-1,3-thiazole-4-carboxamide.

From 2-phenyl-N-(2-piperidin-4-ylphenyl)-1,3-thiazole-4-carboxamide and each corresponding starting material, in the same manner as in Example 1065, the compounds of Examples 1053 to 1091 were prepared.

Example 1116 To a solution of 2.2 mg of propionic acid in 60 l of 1-methylpyrrolidin-2-one were added 12.5 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-1-yl]phenyl}-2-piperidin-4-y1-1,3-thiazole-4-carboxamide dihydrochloride, 10.4 l of triethylamine, a solution of 3.4 mg of HOBt in 1.00 ml of N,N-dimethylformamide, and 100 mg of PS-Carbodiimide (Argonaut Technologies, Inc.) at room temperature, followed by stirring overnight. To the reaction liquid were added 50 mg of MP-Carbonate (Argonaut Technologies, Inc.) and 50 mg of PS-Isocyanate (Argonaut Technologies, Inc.) at room temperature, followed by stirring for 4 hours, and the insolubles were filtered. The filtrate was concentrated under reduced pressure to prepare 10.4 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-1-yl]phenyl-}2-(1-propionylpiperidin-4-yl)-1,3-thiazole-4-carboxamide.
In the same manner as in Example 1116, the compounds of Examples 1116 to 1161 were prepared using the corresponding carboxylic acid as a starting material.
Example 1162 To a solution of 1.7 mg of propionaldehyde, 12.5 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-1-yl]phenyl}-2-piperidin-4-yl-1,3-thiazole-4-carboxamide dihydrochloride, and 6.9 l of triethylamine in 0.50 ml of N,N-dimethylformamide were added 50 l of acetic acid and 75 mg MP-Triacetoxyborohydride (Argonaut Technologies, Inc.) at room temperature, followed by stirring overnight. To the reaction liquid was added 50 mg of PS-Isocyanate (Argonaut Technologies, Inc.) at room temperature, followed by stirring for 4 hours, and the insolubles were filtered.
The filtrate was purified by solid phase extraction using BondElut SCX (Varian, Inc., USA) (eluent, concentrated aqueous ammonia:methanol=1:9) to prepare 0.9 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-1-yl]phenyl}-2-(1-propylpiperidin-4-yl)-1,3-thiazole-4-carboxamide.
In the same manner as in Example 1162, the compounds of Examples 1162 to 1177 were prepared using the corresponding aldehyde as a starting material.
Example 1178 To 3.4 mg of methanesulfonylchloride was added a mixed solution of 12.5 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-1-yl]phenyl}-2-piperidin-4-yl-1,3-thiazole-4-carboxamide dihydrochloride and 10.4 l of triethylamine in 0.50 ml dichloroethane and 0.50 ml of N,N-dimethylformamide at room temperature, followed by stirring overnight. To the reaction liquid were added 50 mg of PS-Isocyanate (Argonaut Technologies, Inc.) and 50 mg of PS-Trisamine (Argonaut Technologies, Inc.) at room temperature, followed by stirring for 4 hours, and the insolubles were filtered. The filtrate was purified by solid phase extraction using BondElut SCX (Varian, Inc., USA) (eluent, concentrated aqueous ammonia:methano1=1:9) to prepare 11.4 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-l-yl]phenyl}-2-(1-(methylsulfonyl)piperidin-4-yl)-1,3-thiazole-4-carboxamide.

In the same manner as in Example 1178, the compounds of Examples 1178 to 1195 were prepared using the corresponding sulfonyl chloride as a starting material.

Example 1196 To 2.6 mg of isopropylisocyanate was added a solution of 12.5 mg of N-{2-[4-(2-amino-2-oxoethyl)piperazin-l-yl]phenyl}-2-piperidin-4-yl-1,3-thiazole-4-carboxamide dihydrochloride and 10.4 l of triethylamine in 0.50 ml of N,N-dimethylformamide at room temperature, followed by stirring overnight. To the reaction liquid were added 50 mg of PS-Isocyanate (Argonaut Technologies, Inc.) and 50 mg of PS-Trisamine (Argonaut Technologies, Inc.) at room temperature, followed by stirring for 4 hours, and the insolubles were filtered. The filtrate was purified by solid phase extraction using BondElut SCX (Varian, Inc., USA) (eluent, concentrated aqueous ammonia:methanol=1:9) to prepare 11.9 mg of 4-{4-[({2-[4-(2-amino-2-oxoethyl)piperazin-l-yl]phenyl}amino)carbonyl]-1,3-thiazol-2-yl}-N-isopropylpiperidine-1-carboxamide.
In the same manner as in Example 1196, the compounds of Examples 1196 to 1202 were prepared using the corresponding isocyanate or isothiocyanate as a starting material.

The structures and the physiochemical data of the compounds of Examples 1 to 1202 are shown in Tables 6 to 68. In addition to the description on the preparation methods in Examples as above, the compounds of the Example Nos. were prepared in the same manner as the methods of Examples of the numbers shown in Syn of Tables, using each corresponding starting material.

In the tables as described below in Examples, the following abbreviations are used.

Ex in the left-hand columns in the Tables represents Example Nos., and the cells in the middle columns except for the top cell of each table show the structural formulae corresponding to the substituents of the compounds of the present invention represented by the general formulae. The structural formulae marked with * in the cells of the tables indicate that the compounds are optically active.
Example Nos. with reference to the preparation methods with Syn are shown at the tops of the right-hand columns. The materials horizontally described in the right hand of Syn, that is, (Sal) indicate salts, and the materials without such a description represents free compounds.

(HC1) represents hydrochloride, and (Na) represents a sodium salt. The values by mass analysis as Dat (physiochemical data) are shown at the bottoms in the right-hand columns.

[Table 6]

A N -N
H c15 Ex Q p` Syn (Sal) H2NOC }-, -* 501 (HCI) Dat 9 NN MS(FAB) m/z:
Me 450 ([M+H]+) _ n 501 (HCI) 1 Me uN MS(FAB) m/z: H~~ 501 (HCI) 379 ([M+H]+) 10 Me-N N MS(FAB) m/z:
HN N p 146 (HCI) Me0 C 409 ([M+H]+) 2 MS(FAB) m/z: H NOC _ 2 j 234 365 ([M+H]+) 1 1 2 LN N MS(API) m/z:
MeO 185 (HCI) 494 ([M+H]+) 3 N N MS(FAB) m/z: H NOCH0A C 36 (Na) 423 ([M+H]+) 12 2 L N N MS(FAB) m/z:
Et02C ~ - 191 (HCI) 480 ([M+H]+) 4 LN`N \/ MS(FAB) m/z: H 2 NOC H2NOC 167 (HCI) ~
451 ([M+H]+) 13 LNN MS(ESI) m/z:
H02C _ 36 (HCI) 479 ([M+H]+) L UN \/ MS(FAB) m/z: H2NOC Et02C 501 423 ([M+H]+) 14 N MS(ESI) m/z:
H2NOC `-.1 - 167 (HCI) 522 ([M+H]+) 6 L ~N \/ MS(FAB) m/z: HzNOC H02C 36 (Na) 422 ([M+H]+) 15 N'jN5:p MS(FAB) m/z:
Me H2 NOC 501 (HCI) H NOC 494 ([M+H]+) ~
7 NN NP/ MS(FAB) m/z: H2NOC 2 167 (HCI) Me MS(ESI) m/z:
r 450 ([M+H]+) 16 493 ([M+H]+) Me * -501 (HCI) Me-N N~ ~ 17 8 H2NOC\-N N9 MS(FAB) m/z: 17 ~ MS(ESI) m/z:
450 ([M+H]+) CO2H 423 ([M+H]+) Me Me_ JN ~/ 234 (HCI) M~N N 28 18 ~ CONH MS(ESI) m/z: 28 0 MS(FAB) m/z:
2 422 ([M+H]+) 407 ([M+H]+) H2N LN - 234 (HCI) EtO N - 29 19 \/ MS(FAB) m/z: 29 ~ N~ MS(FAB) m/z:
440 ([M+H]+) 437 ([M+H]+) H2NOC F 234 (HCI) n 501 20 L v MS(FAB) m/z: 30 /N -= N
MS(FAB) m/z:
440 ([M+H]+) Boc 465 ([M+H]+) H2NOC _ F 234 (HCI) Me, ,~ - 31 21 L~ \/ MS(FAB) m/z: 31 O iS N\ N MS(FAB) m/z:
440 ([M+H]+) O 443 ([M+H]+) H2NOC f--\ 234 (HCI) 0 501 22 LN N F MS FAB m/z: 32 HN
( ) --/ N MS(ESI) m/z:
440 ([M+H]+) 379 ([M+H]+) H2NOC ,-~ _ Cl 234 (HCI) 0 _ 234 (HCI) 23 L NN \/ MS(FAB) m/z: 33 Me-N N
456 ([M+H]+) ~ \ / MS(FAB) m/z:
393 ([M+H]+) H 2 NOC 234 (HCI) L r-, - H 2NOC _ 501 (HCI) 24 ~ \/ CI MS(FAB) m/z: 34 LNaN
456 ([M+H]+) \ / MS(FAB) m/z:
434 ([M+H]+) H2NOC L _ Me 234 (HCI) - 501 25 N,N MS(FAB) m/z: 35 EtO2C-~N \/
MS(FAB) m/z:
436 ([M+H]+) 436 ([M+H]+) H2NOC ~ _ 234 (HCI) -26 NvN\/ Me MS(FAB) m/z: 36 HO C~N 36 (Na) 2 \/ MS(FAB) m/z:
436 ([M+H]+) 408 ([M+H]+) H2NOC ~ MeO 234 (HCI) _ 501 27 LNN MS(FAB) m/z: 37 H2NOC~N \/ MS(ESI) m/z:
452 ([M+H]+) 407 ([M+H]+) HN/Me _ 167 Et02C 501 38 ~j~N \/ MS(FAB) m/z: 48 CN-P MS(ESI) m/z:
O
421 ([M+H]+) 436 ([M+H]+) N-Me _ 167 HO 2C
Me- _ 36 39 O~N \/ MS(FAB) m/z: 49 CN \/ MS(FAB) m/z: 435 ([M+H]+) 408 ([M+H]+) 40 HN MS(ESI) m/z: 50 ~MS(FAB) m/z:
O 451 ([M+H]+) 407 ([M+H]+) MeO ~ 167 HO 501 41 HN N\ i MS(ESI) m/z: 51 CN-P MS(ESI) m/z:
0 465 ([M+H]+) 380 ([M+H]+) ok Et0 42 ~-CN MS(FAB) m/z: 52 N\/ MS(FAB) m/z:
O p 475 ([M+H]+) 450 ([M+H]+) HO2C _ 36 N _ 167 53 ~N \ / MS(FAB) m/z:
43 O~N \/ MS(FAB) m/z: 422 ([M+H]+) 477 ([M+H]+) H2NOC _ 167 167 (HCI) 54 ~N \/ MS(FAB) m/z:
e 44 ON M
` ~N MS(FAB) m/z: 421 ([M+H]+) ~ ~J
p 490 ([M+H]+) C02Me p 501 45 HO~N \ ~ 501 55 N MS(FAB) m/z:
MS(FAB) m/z: 465 ([M+H]+) 380 ([M+H]+) H2NOC

46 MS(FAB) m/z: ~_~ 501 OH 396 ([M+H]+) 56 N MS(FAB) m/z:
OH _ 501 1--' 450 ([M+H]+) 47 ~N \ / H2NOC
MS(FAB) m/z:
OH 410 ([M+H]+) ~~ 36 (Na) 65 ~rN \/ MS(FAB) m/z:
57 ci) MS(FAB) m/z: HO 382 ([M+H]+) 451 ([M+H]+) H2NOC Hp 501 CONH 66 rN MS(ESI) m/z:
Q 2 63 HO 382 ([M+H]+) 58 (V MS(FAB) m/z:
432 ([M+H]+) HO,,, _ * 501 NC 67 N ~ / MS(FAB) m/z:
N C-_,CN 63 HO 382 ([M+H]+) 59 \/ CN MS(FAB) m/z: H02C - 68 414 ([M+H]+) 68 ~N MS(FAB) m/z:
CO2Me 394 ([M+H]+) 60 N MS(FAB) m/z: 69 MS(FAB) m/z:
479 ([M+H]+) 393 ([M+H]+) 70 Me02C MS(FAB) m/z:
501 394 ([M+H]+) 61 N MS(FAB) m/z:
464 ([M+H]+) HOZC-<~N 36 Na H2NOC 71 MS(ESI) m/z:
CO2H 380 ([M+H]+) 36 (Na) HO-CN - 501 62 N MS(FAB) m/z: 72 \/ MS(FAB) m/z:
~ 465 ([M+H]+) 394 ([M+H]+) H2NOC ~ - 501 (HCI) CN 63 73 rN,,_~ MS(FAB) m/z:
63 MS(FAB) m/z: CONH2 436 ([M+H]+) ~-N
NC 428 ([M+H]+) /---\ - 501 74 0 N \ / MS(FAB) m/z:
64 H ~N MS(FAB)1m/z: 366 ([M+H]+) 366 ([M+H]+) /- - 501 85 (HCI) 75 v ~/ MS(ESI) m/z: 85 HO MS(FAB) m/z:
382 ([M+H]+) N 408 ([M+H]+) /~ - 76 NC 185 (HCI) 76 O-Sv \/ MS FAB m/z: -N
( ) 86 MS(FAB) m/z:
398 ([M+H]+) 403 ([M+H]+) O ~ /~ - 77 OH 501 77 U \/ MS(FAB) m/z: 87 iN \/ MS(FAB) m/z: CY 414 ([M+H]+) Boc 480 ([M+H]+) 78 p= N+ \/ MS(FAB) m/z: 88 HN MS(FAB) m/z:
414 ([M+H]+) 380 ([M+H]+) N 501 H2NOC HO _ 185 (HCI) 79 MS(FAB) m/z: 89 L N ~ MS(ESI) m/z:
Boc 464 ([M+H]+) 435 ([M-H]-) - 146 (HCI) Boc_N 501 80 HN ~/ MS(FAB) m/z: 90 MS(FAB) m/z:
364 ([M+H]+) 450 ([M+H]+) 99 N \/ MS(FAB) m/z: HN - 146 (HCI) 81 HZ ~N
91 \ / MS(FAB) m/z:
407 ([M+H]+) 350 ([M+H]+) 82 N MS(FAB) m/z: 92 MS(FAB) m/z:
477 ([M+H]+) 393 ([M+H]+) / 185 (HCI) 167 93 H2NO~ MS(FAB) m/z:
83 pC~, N MS(FAB) m/z: N 407 ([M+H
]+) p 476 ([M+H]+) H2NOC 185 (HCI) 9CI) 84 LN MS(ESI) m/z: 94 N MS(FAB) m/z:
2( 498 M+H +
421 ([M+H]+) MeO2C (L ] ) HN 95 H2NOLCN 185 (HCI) 95 MS(ESI) m/z: 101 MS(FAB) m/z:
MeO2C 408 ([M+H]+) 419 ([M+H]+) CONH NC - 185 (HCI) ~ 185 102 LN / \ / MS(FAB) m/z:
96 N2 Q MS(FAB) m/z: 401 ([M+H]+) MeO2C 465 ([M+H]+) N- 234 (HCI) 501 103 H NOC~N \/ MS(ESI) m/z:
97 ON D MS(FAB) m/z: 2 408 ([M+H]+) Boc 462 ([M+H]+) `-' _N 234 (HCI) - 146 (HCI) 104 H 2 NOC N \/ MS(ESI) m/z:
98 HN / \/ MS(FAB) m/z: 408 ([M+H]+) 362 ([M+H]+) 234 (HCI) 105 /CN \ iN MS(ESI) m/z:

99 HN N MS(FAB) m/z: AC 408 ([M+HI+) 405 ([M+H]+) \ O 28 0 / \
106 Ac-N MS(FAB) m/z:
100 464([M+H]+) 100 ~N N I MS(FAB) m/z:
0 475 ([M+H]+) [Table 7]

A N -N C ~ ~ ~N
H S

Q

Q iy Syn (Sal) H2NO~ ~ 234 (2HCI) Ex 115 V CI MS(ESI) m/z:
Dat 457 ([M+H]+) 119 (2HCI) H2NOC Me 234 (2HCI) 107 Me-N 116 L^N N
MS(FAB) m/z: MS(ESI) m/z:
380 ([M+H]+) 437 ([M+H]+) 0 501 (HCI) H2NOC 234 (2HCI) 108 H vN 117 MS(FAB) m/z: L~ Me MS(ESI) m/z:
~
380 ([M+H]+) 437 ([M+H]+) H2NOC ~ - 501 (2HCI) H2NO~ MeO 234 (2HCI) L 109 UN MS(FAB) m/z: 118 NN MS(ESI) m/z:

423 ([M+H]+) 453 ([M+H]+) H2N L n - 234 (2HCI) - 119 (HCI) 110 ~ \/ MS(FAB) m/z: 119 H2NOC-~N \/ MS(FAB) m/z:

F 441 ([M+H]+) 408 ([M+H]+) H2N0 L~ F 234 (2HCI) O 76 111 ~ MS(ESI) m/z: 120 H2NOC~N MS(ESI) m/z:
441 ([M+H]+) 424 ([M+H]+) H2NOC ~ _ F 234 (2HCI) - 119 112 L~ MS(FAB) m/z: 121 Et02C-CN ~/ MS(FAB) m/z:
441 ([M+H]+) 437 ([M+H]+) H2NOC ~ 234 (2HCI) - 36 113 LNN \/ F MS(FAB) m/z: 122 HO2C-CN MS(FAB) m/z:
441 ([M+H]+) 409 ([M+H]+) H2NOC Cl 234 (2HCI) HO - 501 (HCI) 114 MS(ESI) m/z: 123 MS(FAB) m/z:
457 ([M+H]+) HO 383 ([M+H]+) H2NO L 501 (2HCI) 234 2HCI
124 N/ MS(ESI) m/z: 127 H NOC `-'N MS(FAB) m/z:
420 ([M+H]+) 2 409 ([M+H]+) H2NOC 501 (2HCI) 501 (2HCI) 125 LN MS(ESI) m/z: 128 ~N N
H2NOC MS(ESI) m/z:
422 ([M+H]+) 409 ([M+H]+) N- 234 (2HCI) H2NOC ~ N- 501 (3HCI) 2 NOC/CIN MS(ESI) m/z: 129 L UN MS(FAB) m/z:
409 ([M+H]+) 424 ([M+H]+) [Table 8]

q N

H
~H___ Q q Syn (Sal) H2NOC l N 501 (HCI) Ex Dat 134 LN~ MS(ESI) m/z:
453 ([M+H]+) H2NO L/- 130 (HBr) H NOC F 501 (HCI) 130 N,N MS(ESI) m/z: 135 2 LNN MS(ESI) m/z:
439 ([M+H]+) 471 ([M+H]+) H2N0 L~ F- 501 (HCI) 501 131 N N\/ MS(FAB) m/z: 136 H NOC~N MS(ESI) m/z:
457 ([M+H]+) 2 424 ([M+H]+) C H2NOC ~ _ F 501 (HCI) H2NO L 501 (HCI) 132 LN N\/ MS FAB m/z: 137 N/
v ( ) MS(ESI) m/z:
457 ([M+H]+) 436 ([M+H]+) H NOC 501 (HCI) H2NOC - 501 (HCI) 133 2 Ll F MS(FAB) m/z: 138 LN \/ MS(ESI) m/z:
457 ([M+H]+) 438 ([M+HI+) N- 501 (HCI) 501 (HCI) L39 ~N MS(ESI) m/z: 140 ~N \~N MS(ESI) m/z:

425 ([M+H]+) 2 425 ([M+H]+) [Table 9]

A
N
N ci H -S N
Q

Ex Q A Syn (Sal) Dat 141 H2NOCPN \ / MS(FAB) m/z:
442 ([M+H]+) 142 NC-CN \ / MS(FAB) m/z:
424 ([M+H]+) [Table 10]

A N
N
H C \ ~ NN
S

Q

Q A Syn (Sal) N~ ~ 501 (HCI) Ex 144 H NOC~ MS(ESI) m/z:
Dat 2 409 ([M+H]+) H2NOC 501 (HCI) N- 501 (HCI) 143 L UN MS(ESI) m/z: 145 /CN MS(ESI) m/z:
424 ([M+H]+) H 2 NOC 410 ([M+H]+) [Table 11]

A N

}_ ~O
H cs \
QT

Ex Q p` Syn (Sal) H2NOC 501 (HCI) Dat 154 LN~ MS(FAB) m/z:
Me 459 ([M+H]+) HN N \/ 146 (HCI) Me0 C ~[c 146 MS(ESI) m/z: 2~ _ 501 374 ([M+H]+) 155 Boc-N N MS(FAB) m/z:
~--~ _ 501 532 ([M+H]+) 0 147 HN N\/ MS(FAB) m/z: MeO2C ~[c _ 501 u 388 ([M+H]+) 156 Boc-N JN \/ MS(FAB) m/z:
n - 501 532 ([M+H]+) N N \ ~
148 Boc U MS(FAB) m/z: Me02 r_\~c 146 (HCI) 474 ([M+H]+) 157 HN N MS(FAB) m/z:
EtO2C/---\ _ 185 432 ([M+H]+) 149 L~ \/ MS(FAB) m/z: Me02C
= * _ 146 HO C 460 ([M+H]+) 158 HN MS(ESI) m/z:
2 /--\ 36 (Na) 432 ([M+H]+) 150 LUN \/ MS(ESI) m/z: Me02C ~c 432 ([M+H]+) 191 (HCI) H NOC _ 159 Me-N NMS(FAB) m/z:
z: 446 ([M+H]+) 151 2 L N MS501 (FAB) ml u 431 ([M+H]+) H02C * P 36 H2NOC,-- _ 501 (HCI) 160 Me-N~ MS(ESI) m/z:
152 L~ \ ~ MS(FAB) m/z: 432 ([M+H] ) Me 459 ([M+H]+) H2N ~ 0 501 Me 161 IV N \ ~ MS(ESI) m/z:
H2NOC ;~ _ 501 (HCI) ]+
153 LN ~ ~ ~ MS(FAB) m/z: 445 ([M+H ) Me 459 ([M+H]+) NH2 185 (HCI) o1 O~ i--~ - i ~ 167 (2HCI) 162 Me vN ~/ MS(ESI) m/z: 172 ~N
~ (-N~ MS(FAB) m/z:
445 ([M+H]+) p-,J NJ 544 ([M+H]+) Me `NH 167 (HCI) ~ 100 163 0 ~ ~ ~/ MS(FAB) m/z: 173 Nr~N MS(FAB) m/z:
445 ([M+H]+) 0 487 ([M+H]+) Me~Me 167 (HCI) OAc rN ~ I 28 164 O~ MS(FAB) m/z: 174 ~-N J MS(FAB) m/z:
459 ([M+H]+) 0 474 ([M+H]+) 167 (HCI) Me0 _ 28 165 N ~N MS(FAB) m/z: 175 ~-N N ~/ MS(FAB) m/z:
O~N`J 485 ([M+H]+) 0 446 ([M+H]+) ~ 167 ( 0 ) ~ 167 (HCI) N MS(FAB) m/z: NJ ~
O~ N J 176 N N MS(FAB) m/z:
483 ([M+H]+) ~ J
0 0 501 ([M+H]+) 167 (HCI) N-Me 167 CNJ N MS(FAB) m/z: l 167 2HC1 ( ) O~ N J 501 ([M+H]+) 177 N J N MS(FAB) m/z:
~NJ
~N-Me 167 (2HCI) O 514 ([M+H]+) 168 N Jr--\MS(FAB) m/z: p,~ ~p O~N~ 514 ([M+H]+) ~S~ 167 (HCI) 178 NN J y MS(ESI) m/z:
HONN ( H 169 (HCI) p 549 ([M+H]+) 169 ~N MS(FAB) m/z: NC
O~'N`J 517 ([M+H]+) LN N - 185 (HCI) 179 u \ ~ MS(ESI) m/z:
p 167 (HCI) 413 ([M+H]+) 170 ~N J MS(FAB) CN
p _ 515 ([M H]+) 180 ~N N 185 (HCI) MS(FAB) m/z:
N 167 (HCI) 427 ([M+H]+) 171 N N MS(FAB) m/z: CONH2 185 (HCI) J
499 ([M+H]+) 181 (-N NMS(ESI) m/z:
J 445 ([M+H]+) N, 185 (2HCI) H2NOC --- \ F_ 234 (HCI) 182 MS(FAB) m/z: 193 L~ \/ MS(ESI) m/z:
465 ([M+H]+) 449 ([M+H]+) 191 (HCI) H2NOC ^ _ F 234 (HCI) 183 MS(FAB) m/z: 194 L ~ \/ MS(FAB) m/z:
455 ([M+H]+) 449 ([M+H]+) 185 (HCI) NOC N N F 234 (HCI) 184 SN rN MS(FAB) m/z: 195 MS(FAB) m/z:
471 ([M+H]+) 449 ([M+H]+) 185 (HCI) HZNOC
N N_ 501 (HCI) L
185 ~O'N ~N MS(FAB) m/z: 196 MS(ESI) m/z:
N~'NJ 456 ([M+H]+) F 449 ([M+H]+) O 185 (HCI) H2NOC ~ F F 501 (HCI) 186 HNNNHN J MS(FAB) m/z: 197 LN MS(FAB) m/z:
471 ([M+H]+) 467 ([M+H]+) 185 (2HCI) H2NOC ^ F _ 501 (HCI) 187 N N J MS(ESI) m/z: 198 L ~ \/ F MS(FAB) m/z:
Me 468 ([M+H]+) 467 ([M+H]+) r01 185 (2HCI) HZN ~^ _ CI 234 (HCI) 188 `NJ ~`N I MS(FAB) m/z: 199 vN \/ MS(ESI) m/z:
~,N`_lj 487 ([M+H]+) 465 ([M+H]+) O
( 185 (2HCI) H2N ~N N CI 234 (HCI) 189 ` N MS FAB m/z: 200 MS(FAB) m/z:
( ) 501 ([M+H]+) 465 ([M+H]+) H 2 NOC Br 185 (2HCI) 201 LN ~N \/ MS(ESI) m/z:
190 N ON MS(ESI) m/z: ([ ]+) Me 485 ([M+H]+) Me 509 M+H
HZNOC ^ _ 234 (HCI) 191 (HCI) 202 L ~
~ \ / MS(FAB) m/z:
191 NliN MS(ESI) m/z: 445 ([M+H]+) O~ 458 ([M+H]+) ~ Me O - 192 (HCI) ~N 501 (HCI) ~--N N\/ 203 N J MS(FAB) mlz:
192 ~--~ MS(ESI) m/z: ~ +
OH + CONH2 445 ([M+H] ) 460 ([M+H] ) H2NOC ~ Me0 234 (HCI) HO~N 36 (Na) 204 LN N \/ MS(ESI) m/z: 213 O MS(FAB) m/z:
461 ([M+H]+) 417 ([M+H]+) H2NOC / NC _ 501 (HCI) HzN~N 501 205 ~-N N\/ MS(FAB) m/z: 214 0 MS(FAB) m/z:
456 ([M+H]+) 416 ([M+H]}) H2NOC ~ NC 206 (HCI) 0/ ~N 501 (HCI) 206 L vN \/ MS(API) m/z: 215 ~ MS(FAB) m/z:
456 ([M+H]+) 458 ([M+H]+) H2N ~N N~ CN 501 (HCI) H~-/ 0 N N- 501 (HCI) 207 ~ MS(ESI) m/z: 216 ~ \~ MS(FAB) m/z:
456 ([M+H]+) 471 ([M+H]+) HO
SOMe 501 N
~~ 501 (HCI) 217 OH MS(ESI) m/z:
208 N~ MS(ESI) m/z: 419 ([M+H]+) HZNOC, 493 ([M+H]+) 501 S02Me 218 CONH2 MS(FAB) m/z:
501 (HCI) 402 ([M+H]+) 209 N) MS(ESI) m/z: 219 HO 501 )TN H2NOC > 509 ([M+H] ) HO MS(FAB) m/z:
391 ([M+H]+) SO2NH2 - 501 (HCI) 501 (HCI) 220 ~N \~ MS ESI m/z:
210 ~N MS(ESI) m/z: CONH2 ( ) ~ 445 ([M+H]+) N > 510 ([M+H]+) H2NOC F - 501 (HCI) H NOC 501 (HCI) 221 N/N MS(ESI) m/z:
211 z LNaN \ / - MS(FAB) m/z: CONH2 463 ([M+H]+) 443 ([M+H]+) 501 N EtO N\/ 501 222 Boc D MS(ESI) m/z:

212 O~ MS(FAB) m/z: 471 ([M+H] ) 445 ([M+H]+) 146 (HCI) 223 HN MS(ESI) m/z:
371 ([M+H]+) H2NOC 185 (HCI) N- 501 (HCI) 224 LN / \/ MS(FAB) m/z: 235 HO-~N MS(FAB) m/z:
428 ([M+H]+) 390([M+H]+) H2NOC 501 (HCI) HO 501 225 LN F MS(FAB) m/z: 236 CN-P MS(FAB) m/z:
446 ([M+H]+) Me02C 447([M+H]+) ~ OMe HO 36 ~ ~ 501 (HCI) N
226 `N ~ MS(ESI) m/z: 237 HO2C MS(API) m/z:
CONHZ 458 ([M+H] ) 433([M+H] ) H NOC

2 LN MS(ESI) m/z: 238 H MS(FAB) m/z:
430 ([M+H]+) O NH2 432([M+H]+) v N- 234 (HCI) O * 167 (HCI) 228 H NOC CN MS(FAB) m/z: 239 Me-N N MS(ESI) m/z:
2 417 ([M+H]+) 431([M+H]+) ~ -N 234 (HCI) N_ 229 H NOC N\/ MS(FAB) m/z: N/ 501 (2HCI) 2 240 O~ MS(ESI) m/z:
417 ([M+H]+) NH2 429([M+H]+) 501 (HCI) F
H NOC N MS(FAB) m/z: O N_ 501 (HCI) 2 417 ([M+H]+) 241 H ~- CN MS(FAB) m/z:
2 N 435([M+H]+) N- 501 (HCI) 231 CN \ / F F
H NOC MS(FAB) m/z: ~--~ N_ 501 (2HCI) 2 435 ([M+H]+) 242 -N~ \/ MS(ESI) m/z:
H2N ~~ N- 501 (2HCI) N H2 450([M+H]+) 232 N~N \~ MS(FAB) m/z: CN
432 ([M+H]+) n p 501 (HCI) Me0 243 ~NN F MS(FAB) m/z:
H2NOC ~ oN-/ 501 (HCI) O N H 474([M+H]+) 233 LN NMS(ESI) m/z: Z
462 ([M+H]+) F IICN 501 (HCI) HO 234 (HCI) 244 ~ ~ \MS(ESI) m/z:
L ~N N 0 NH2 474(LM+HI+) 234 MS(FAB) m/z:
OH 420 ([M+H]+) N~ N- 501 (2HCIl CO2Me _ 501 245 \--~N F MS(FAB) m/z: 254 N ~~ MS(FAB) m/z:
O NH2 450([M+H]+) HO F 466([M+H]+) 501 (HCI) Me 723 246 N MS(FAB) m/z: 255 N~jN /\ MS(FAB) m/z:
~N H 442([M+H]+) ~
Z 0 NH2 459([M+H]+) / ~ 501 247 )CN MS(ESI) m/z: 256 N MS(FAB) m/z:
CO2Me 448([M+H]+) CO2Et 446([M+H]+) HO CN N- 36-167 (HCI) / \

248 O ~ MS(ESI) m/z: 257 QN
_ F MS(FAB) m/z:
NH2 431([M-H]-) CO2Et 463([M+H]+) NC
~ N 501 O
~-C - P N 36 (Na) 249 NN MS(ESI) m/z: 258 N MS(FAB) m/z:
O~ N H 471([M+H]+) 418([M+H]+) CN 501 N ~ ~ 36 250 MS(FAB) m/z: 259 - C02H F MS(FAB) m/z:
435([M+H]+) ~NH2 446([M+H]+) Me O ' CN-P 723 (HCI) V-KNH2 723 260 N NH 2 MS(ESI) m/z:
251 /N MS(ESI) m/z: ~ 473([M+H]+) Me ~N 445([M+H]+) 0 0 N~N ~ ~ ~ 501 ~NH 723 (HCI) 261 ~NH Me MS(ESI) m/z:
252 MeN 2 MS(ESI) m/z: O 2 461([M+H]+) CN 459([M+H]+) N _ 36 C02Me F 501 262 )~~N\~ MS(FAB) m/z:
N - 452([M+H]+) 253 ~~ MS(ESI) m/z: OH
HO 466([M+H]+) CO2H N- 36 p 7N-P/ Cl 501 263 rN-\\` MS(ESI) m/z: 272 MS(FAB) m/z:
OH 450([M-H]-) 451([M+H]+) 0 NH2 N F 167 0 NH ~nj_ ci 501 264 NMS(ESI) m/z: 273 N N MS(ESI) m/z:
HO 451([M+H]+) 466([M+H]+) p NH2 p NH2 167 N _ Me 501 265 N NYF MS(ESt) m/z: 274 N MS(FAB) m/z:
HO 451([M+H]+) 431([M+H]+) p\ Me p TNH2 N- Me 501 / 0 266 275 N N\/ MS(FAB) m/z:
266 H N N- MS(FAB) m/z: ~ 446([M+H]+) O'~ \ / F 512([M+H]+) O N H2 Br OH N_ 501 N F 267 276 N MS(ESI) m/z:
/
267 tN MS(FAB) m/z: 495([M+H]+) HO 438([M+H]+) 0 NH2 N-OH 267 Br 501 OH 277 l-N N MS(ESI) m/z:
CN U \ /
268 N F MS(FAB) m/z: 510([M+H]+) HO 438([M+H]+) 0 NH2 HO O 36 (Na) _ 501 278 N MS(ESI) m/z:
269 MS(FAB) m/z: 461 M+H +
([ l ) HO 375([M+H]+) N -p NH2 MeO2C Hp N 501 501 279 MS(ESI) m/z:
270 N\~ MS(FAB) m/z: CO2Me 462([M+H]+) 475([M+H]+) p NH2 O NHtN N 2N 167 O
N- CN 501 280MS(ESI) m/z:
271 N\/ MS(ESI) m/z: 460([M+H]+) 442 ([M+H]+) CONHZ C02Et 281 II?NNL j MS(ESI) m/z: 290 N\/ MS(ESI) m/z:
CN 468([M+H]+) 479([M+-I]+) 281 * N \ 234 N
282 ~N NMS(ESI) m/z: 291 N _ MS(ESI) m/z:
)D/ ~CN 483([M+H]+) HO 406([M+H]+) O NH2 CI 501 0 NH 2 Me 287 ~
283 N MS(ESI) m/z: 292 N N MS(ESI) m/z:
/ 451([M+H]+) 459([M+H]+) NH O Me Br 501 NH2 ~
rN ~ ~~ -284 MS(ESI) m/z: 293 N N~/ MS(ESI) m/z:
509([M+H]+) 475([M+H]+) O NH2 Me~lO 501 O NH2 0 501 285 N N MS(ESI) m/z: 294 N\ MS(ESI) m/z:
/ 447[M+H]+) Me 447([M+H]+) 295 MS(ESI) m/z:
286 ~N N N MS(ESI) m/z: HO 434 M+H +
~, \ / ([ l) 485([M+H]+) O NH2 HO N 267 O NH2 NNC 287 296 N MS(ESI) m/z:
287 N MS(ESI) m/z: 447([M+H]+) 470([M+H]+) O NH2 H2C 288 297 t N N - MS(ESI) m/z:
_ 288 ~ \ / \ MS(ESI) m/z: \ / 522([M+H]+) 457([M+H]+) N,Me COZEt Me 501 CNI 167 475 M+H MS(ESI) m/z:
289 O MS(ESI) m/z: 298 ~3D/ N
+) 0 500([M+H]+) ([ l COZH Me 36 ~ NH2 F3C
\ 501 299 0 MS(ESI) m/z: 302 N N 0 MS(FAB) m/z:
445([M+H]+) 515([M+H]+) CO2H _ 36 HO

300 N~/ CI MS(ESI) m/z: 303 ~N C MS(ESI) m/z:
451([M+H]+) CO2H 448([M+H]+) 301 NH2 MS(ESI) m/z:
O,~- rN 473([M+H]+) N-,) [Table 12]

A
N N
H S ~--No Q

Ex Q A Syn (Sal) 307 H2N~~N \/ 501 (HCI) Dat O MS(FAB) m/z:
414 ([M+H]+) n - 501 (HCI) - 501 304 Me-N N MS(FAB) m/z: 308 EtO2C- CN \/ MS(FAB) m/z:
386 ([M+H]+) 443 ([M+H]+) 0 - 501 36 (Na) _ 305 HN N\~ MS(FAB) m/z: 309 H02C N MS(FAB) m/z:
~
386 ([M+H]+) 415 ([M+H]+) H2N O /- _ 356 HCI
306 N \ / MS(FAB) m/z:
429 ([M+H]+) [Table 13]

A N
H N S ~NaOH
Q
o Ex Q A Syn (Sal) q S\
501 (HCI) Dat Me 318 rN MS(ESI) m/z:
H2N ~ 501 (HCI) ONH 523 ([M+H]+) 310 MS(ESI) m/z: 2 O
445 ([M+H]+) ,O
F 501 (HCI) 311 H2N LN N~/ 501 (HCI) 319 N N~ ~ NH2 MS(ESI) m/z:
~ F M+H m/z: CONH 524 ([M+H]+) 463 ([ ]+) 2 H NOC F
2 L ~ 501 (HCI) 312 NN 501 (HCI) MS(FAB) m/z: 320 O-N I
II (N MS(ESI) m/z:
463 ([M+H] ) N ^~ N.J 470 ([M+H]+) H2N L --~ - 501 (HCI) 313 ~\~ F MS(FAB) m/z: N\ 501 (HCI) 463 ([M+H]+) 321 ,_-j MS(FAB) m/z:
H 2 NOC 501 (HCI) CONH2 459 ([M+H]+) 314 N N F MS(FAB) m/z:
C 501 (HCI) 481 ([M+H]+) 322 ~NN MS(ESI) m/z:
H2NOC^ F F 501 (HCI) CONH2 477 ([M+H]+) 315 LN JN \ / MS(FAB) m/z: H - 501 481 ([M+H]+) 323 O~N \~ MS(FAB) m/z:

~ - 501 (HCI) 430 ([M+H]+) 316 ~ CN MS(ESI) m/z: HZN ~ - 501 (2HCI) 470 ([M+H]+) 324 N/ \/ MS(FAB) m/z:
IIO 442 ([M+H]+) S, Me 501 (HCI) H2NOC
317 f N MS(ESI) m/z: L - 501 (2HCI) NJ 507 ([M+H]+) 325 N \/ MS(FAB) m/z:
CONH 2 444 ([M+H]+) H2NOC 501 (HCI) f ~ 36 326 LN F MS(ESI) m/z: 335 N - MS(FAB) m/z:
460 ([M+H]+) C02H 431([M+H]+) q 501 (HCI) 501 m/z: 336 ~N N MS(FAB) m/z:
327 O~ g MS(FAB) ~J
470([M+H]+) ~ 516 ([M+H]+) N- 501 (2HCI) N/\ F 501 328 /CN 337 MS(FAB) m/z:
H 2NOC MS(FAB) m/z: COZEt 477([M+H]+) 431 ([M+H]+) 501 N / ~ F
329 /N-<7N 338 - MS 36 (FAB) m/z:
MS(ESI) m/z:
H2NOC 431 ([M+H]+) CO2H 449([M+H]+) N- 501 (HCI) 501 330 NN \/ F MS ESI m/z: 339 /N-?-? MS(ESI) m/z:
H NOC ( ) Me 2 449 ([M+H]+) C02Et 489([M+H]+) H2NOC _ N_ 501 (2HCI) - 501 331 LNv N MS(FAB) m/z: 340 ~N \/ CI MS(ESI) m/z: 446 ([M+H]+) co 2 Et 493([M+H]+) H NOC MeO 501 (HCI) 36 332 2 LN N N MS(ESI) m/z: 341 ~N MS(ESI) m/z:
\-j \ /
476 ([M+H]+) CO2H Me 461([M+H]+) OH N 501 /N-_-CI 36 333 NMS(FAB) m/z: 342 MS(ESI) m/z:
~ -HO
434([M+H]+) co 2 H 463([M-H]-) 334 MS(FAB) m/z:
CO2Et 459([M+H]+) [Table 14]

q OH
N C N~
H S

Q

H2NOC _ Q q Syn (Sal) 346 L _ N F 501 (HCI) Ex Dat MS(ESI) m/z:
449 ([M+H]+) H2N ~~--~ _ 501 (2HCI) H 2 N L 501(2HCI) 343 ~N \/ MS(ESI) m/z: 347 N/ MS(ESI) m/z:
431 ([M+H]+) 426 ([M-H]") H2NOC~ F 501 (HCI) H2NL - 501 (2HCI) 344 Z~ MS(FAB) m/z: 348 N MS(FAB) m/z:
449 ([M+H]+) 430 ([M+H]+) H2NOC~ F 501 (HCI) N
MS N 501 ~2HCI) 345 LN 349 ~ MS(FAB) m/z:
(FAB) m/z: H2NOC
449 ([M+H]+) 417 ([M+H]+) [Table 15]

q N OH
H ~L, N~
CJ
S
Q

Ex Q q Syn (Sal) 351 H2N Z N N F 501 (2HCI) Dat MS(ESI) m/z:
449 ([M+H]+) H2NOC ~ _ 501 (2HCI) H2NOC 501 (HCI) 350 N N \/ MS(ESI) m/z: 352 LN MS(ESI) m/z:
431 ([M+H]+) 428 ([M+H]+) [Table 16]
O
A N
OAc H N C ~Na S
QT

HzNOC (HCI) 501 Ex Q A Syn (Sal) Dat LN
354 / MS(FAB) m/z:
484 ([M+H]+) H2NOC^ F _ 501 (HCI) 353 LN N\/ MS(FAB) m/z:
505 ([M+H]+) [Table 17]

A N ~ N NMe \~~Me H Sj Q

Ex Q p` Syn (Sal) 359 L ~\-/ F 501 (HCI) Dat MS(ESI) m/z:
451 ([M+H]+) ~ _ 501 H 2 N ~,-~ F 501 (HCI) 355 H vN \~ MS(FAB) m/z: 360 ~ / F MS(FAB) m/z:
390 ([M+H]+) 469 ([M+H]+) H NOC 356 (HCI) H2N ~~ F F 501 (HCI) + 361 MS(FAB) m/z:
356 Z N N MS(FAB) m/z:
u \ /
433 ([M+H]+) 469 ([M+H]+) F H2N ~ Br 501 H2NOC ~ _ 501 (HCI) -357 L~ \/ MS(FAB) m/z: 362 N N\/ MS(FAB) m/z:
451 ([M+H]+) 513 ([M+H]+) HNOC~ - F HzN ~ NC 501 (HCI) 2 501 (HCI) 358 Z N N 363 N~N MS(FAB) m/z:
MS(ESI) m/z: 458 ([M+H]+) 451 ([M+H]+) H2NOC~ NC 206 (HCI) H2N ~ - 501 (HCI) 364 L vN MS(FAB) m/z: 375 N/ \/ F MS(FAB) m/z:
458 ([M+H]+) 448 ([M+H]+) H2 LNOC ~ - 501 (HCI) H2NOC MeO _ 501 (HCI) 365 N5/ CN 376 LN / MS(FAB) m/z:
MS(FAB) m/z:
458 ([M+H]+) 460 ([M+H]+) OMe H2NOC ~ NC _ F 501 (HCI) 501 (HCI) 366 L V MS(FAB) m/z: 377 No' MS(FAB) m/z:
476 ([M+H]+) CONH2 460 ([M+H]+) H2NOC MeO2C 234 H2N~ - 501 (HCI) ~ N MS(FAB) m/z:
367 L~N MS(FAB) m/z: 378 ([M+HI+) 491 ([M+H]+) H 2 NOC 432 501 (HCI) HO C -HO2C ~ 2 _ 36 379 N \/ F MS(FAB) m/z:
368 LN\---/!q MS(ESI) m/z: 450 ([M+H]+) 478 ([M+H]+) 501 (HCI) 501 (HCI) 380 H ~N MS(FAB) m/z:

~N~N J MS(FAB) m/z: 419 ([M+H]+) 458 ([M+H]+) N
` 501 (HCI) H N
2 501 381 "N / F
H2NOC MS(FAB) m/z:
370 O NMS(ESI) m/z: 437 ([M+H]+) 418 ([M+H]+) H NOC
2 f-- ~ N- 501 (HCI) 371 Et02C N501 382 LN~ \/ MS(FAB) m/z:
~ MS(FAB) m/z:
447 ([M+H]+) 434 ([M+H]+) MeO 501 (HCI) 36 H2NOC N_ 372 HO2 C-~N MS(FAB) m/z: 383 LN N MS(FAB) m/z:
\~ \/
419 ([M+H]+) 464 ([M+H]+) H2NOC 501 (HCI) N=\ 234 (HCI) 373 LN / \/ MS FAB m/z: 384 /CN iN MS(FAB) m/z:
( ) H2NOC ~ +
430 ([M+H]+) 420 QM+H] ) N-H2N OC F 501 (HCI) HO-CN 501 (HCI) 374 N 385 MS(FAB) m/z:
/ MS(ESI) m/z: 392([M+H]+) 448 ([M+H]+) O NH2 NH F 501 (HCI) N- 2~ O 2 N-386 N \~ MS(ESI) m/z: 395 N\ ~ MS(FAB) m/z:
HO 449([M+H]+) 437([M+H]+) O NH2 234 (2HCI) ~ ~--~ N 501 (2HCI) 396 N N MS(ESI) m/z:
387 NN F MS(FAB) m/z: U
452([M+H]+) 452([M+H]+) O NH2 234 (2HCI) O NH2 CN 501 (HCI) pN-/ 397 ~N N F MS(FAB) m/z:
388 N \ MS(ESI) m/z: 476([M+H]+) 431([M+H]+) ~f-OH O NHz F NC 501 (HCI) _ 389 * MS(FAB) m/z: 398 NV MS(FAB) m/z:
CN-c1I / 391([M+H]+) 476(IM+HI+) O N H2 MeO
2C 501 N N 501 (2HCI) 390 N\/ MS(FAB) m/z: 399 N~ N\ MS(FAB) m/z:
476([M+H]+) 459([M+H]+) O NH2 HO2C 36 \ 501 (HCI) 391 N\/ MS(ESI) m/z: 400 N MS(FAB) m/z:
462([M+H]+) O NH2 444([M+H]+) O 2 H2N 0 167 501 (HCI) NH
392 N MS(ESI) m/z: 401 ~N ~ MS(FAB) m/z:
O NH
461([M+H]+) 2 444([M+H]+) O NH2 0 NH2 501 (HCI) 167 (HCI) 402 ~NH MS(FAB) m/z:
393 MS(ESI) m/z: +
476([M+H]+) O 2 446([M H]+) HO N~ ~ N- 36-167 (HCI) OH N_ 394 (HCI) 403 O MS(ESI) m/z:
394 MS(ESI) m/z: NH2 435([M+H]+) HO 422([M+H]+) /-\ ~ ~ 501 404 0 N - MS(ESI) m/z:
377([M+H]+) N 723 (HCI) 405 MS(FAB) m/z: 415 Me "'CN MS(ESI) m/z:
391([M+H]+) 447([M+H]+) 501 (HCI) Me 406 N MS(FAB) m/z: N~CONH2 723 (HCI) 416 MS(ESI) m/z:
O NH2 432([M+H]+) CN
461([M+H]+) 407 T-N N N MS(ES )1m/z: 0 N N\ 723 (HCI) \_~ 473([M+H]+) 417 MS(ESI) m/z:
378([M+H]+) 408 N~ MS(FAB) m/z: 418 N MS(FAB) m/z:
450([M+H]+) CO2Et 448([M+H]+) O N H2 F Me 529 N ~N 723 409 MS(ESI) m/z: 419 MS(FAB) m/z:
450([M+H]+) `CONH2 461([M+H]+) N- 501 (2HCI) Me N ~ ~ 723 (HCI) N 420 ~N/ - MS(FAB) m/z:
N
410 MS(ESI) m/z: LCONH2 475([M+H]+) O N H2 448([M+H]+) IXCN__p 501 H N N 501 421 F MS(FAB) m/z:
411 O~ J \/ MS(FAB) m/z: C02Et 465([M+H]+) 404([M+H]+) ~ \ 36 O"/~ N- 501 422 N - F MS(FAB) m/z:
412 H 1N ,_-/ MS(ESI) m/z: CO2H 437([M+H]+) 405([M+H]+) N-HO - 501 423 N MS(FAB) m/z:
413 N\/ MS(FAB) m/z: CO2H 420([M+H]+) HO 421([M+H]+) NC

HO N- 501 424 N NMS(FAB) m/z:
414 N\/ MS(FAB) m/z: ~ HO 422([M+H]+) O NH2 472([M+H]+) * 501 CO2H 36 425 , CN \ / MS(ESI) -) 434 \ ~ CI MS(ESI) m/z:
HO 377([M+H]+) 453([M+H]+) O 1'4 H2 F NC 501 146 (2HCI) 426 N N MS(FAB) m/z: 435 ~N MS(FAB) m/z:
490([M+H]+) N H2 404([M+H]+) O NH2 CI 234 0 NH jIJ'O 501 427 N MS(ESI) m/z: 436 ~~ N ~~ MS(FAB) m/z:
453([M+H]+) N J 475([M+H]+) O NH2 Me,O 501 CONH2 F3C

428 N N MS(ESI) m/z: 437 N N O MS(FAB) m/z:
~
449([M+H]+) 517([M+H]+) C02Et Me 501 ONHz C\ F2 501 429 N \ ~ O MS(ESI) m/z: 438 N N aO MS(ESI) m/z:
477([M+H]+) 499([M+H]+) C02Et _ 501 501 430 \N \/ CI MS(ESI) m/z: 43 HN\ N\/ MS(FAB) m/z:
481([M+H]+) BOC 504([M+H]+) 440 MS(ESI) m/z:
431 ~c N ~ N \ MS(ESI) 234 m/z:
HO 408([M+H]+) CO2Me 448([M-H] ) O ~7N O 501 432 N \MS(ESI) m/z:
Me 449([M+H]+) CO 2H Me\ 36 433 N\ O MS(ESI) m/z:
449([M+H]+) [Table 18]
O
N N j-NjMe H S

T

Q q Syn (Sal) N 501 (HCI) Ex 442 /CN
Dat H2NOC MS(FAB) m/z: 405 ([M+H]+ ) H2NOC N - 356 (HCI) N 441 u \ / MS(ESI) m/z:

419 ([M+H]+) [Table 19]
O
q N
N c , \>~"
H O
Q

Q q Syn (Sal) 36 Na Ex 447 /N_-I MS(FAB) m/z:
Dat HO
2 C 392([M+H]+) Me-N ~ N~ / - 501 (HCI) /~1 /~N - 167 443 u MS(FAB) m/z: 448 H2NOC ~/ MS(FAB) m/z:
363([M+H]+) 391([M+H]+) H2NOC - 501 (HCI) D 501 444 ~ ~N \/ MS(FAB) m/z: 449 HO-~N MS(FAB) m/z:
406([M+H]+) 364([M+H]+) 445 HN~N MS(FAB) m/z: 450 ~N \/ MS(FAB) m/z:
363([M+H]+) HO 366([M+H]+) 501 H2NOC _ 501 (HCI) 446 ~N MS(FAB) m/z: 451 MS(FAB) m/z:
Et02C
420([M+H]+) 405([M+H]+) H2N ~ 501 (HCI) 452 N MS(FAB) m/z:
403([M+H]+) [Table 20]

A N
N ic , ~~ ,- /IV
H O

Q
Ex Q A Syn (Sal) 455 ~N \/ 501 (HCI) Dat H2NOC MS(FAB) m/z:
392([M+H]+) H2NOC~ 501 (2HCI) N- 501 (2HCI) 453 L~ SD MS(FAB) m/z: 456 H2NOC CN / MS(FAB) m/z:
407([M+H]+) 393([M+H]+) H2NOC ~ F 501 (2HCI) 454 N N MS(FAB) m/z:
425([M+H]+) [Table 21]

A -N
H O ~~--Q

Ex Q p` Syn (Sal) H2N OC N F_ 501 (HCI) Dat 458 N \ / MS(FAB) m/z:
426([M+H]+) H2N ~ ~ - 501 (HCI) N 501 457 uN MS(FAB) m/z: 459 H2NOC \/ MS(FAB) m/z:
408([M+H]+) 393([M+H]+) N- 501 (HCI) L60 H z ( NOC~N \/ MS FAB) m/z:
394([M+H]+) [Table 22]

A N
N
~ NN
H

Q
Ex Q A Syn (Sal) 463 /CN \/ 501 Dat H2NOC MS(FAB) m/z:
393([M+H]+) HZN ~ n 501 (HCI) /~N \ D 501 (HCI) 461 u MS(FAB) m/z: 464 H2 NOC/\~ MS(FAB) m/z:
408([M+H]+) 394([M+H]+) H2NOC F 501 (HCI) H2NOC ~ N_ 501 (HCI) 462 L N ~ N MS(FAB) m/z: 465 LNv MS(FAB) m/z:
426([M+H]+) 409([M+H]+) [Table 23]

A
N
H C '}-~

Q

Ex Q A Syn (Sal) 468 ~N \/ 501 (HCI) Dat H2NOC MS(FAB) m/z:
408([M+H]+) HzNOC r--\ _ 501 (HCI) ~ N- 501 (HCI) N
466 MS(FAB) m/z: 469 H2NOC \/ MS(FAB) m/z:
423([M+H]+) 409([M+H]+) H2NOC F _ 501 (HCI) 467 Z N N \ / MS(FAB) m/z:
441([M+H]+) [Table 24]

A N -N ~ \ ~N
O
NHBoc Q

Q A Syn (Sal) /CN 501 Ex Dat 472 H2NOC MS(FAB) m/z:
507([M+H]+) HZN ~ 501 /~N 501 470 u MS(ESI) m/z: 473 H2NOC/~~ MS(FAB) m/z:
522([M+H]+) 508([M+H]+) 471 ~ MS(FAB) m/z:
540([M+H]+) [Table 25]

A
N /N

Q

Ex Syn (Sal) H2NL r--\ F- 146 (2HCI) Dat 475 N N\/ MS(FAB) m/z:
440([IVI+H]+) H2NOC ~ _ 146 (2HCI) N 146 (HCI) 474 ~ \/ MS(FAB) m/z: 476 H2NOC \/ MS(FAB) m/z:
422([M+H]+) 407([M+H]+) ~ N- 146 (2HCI) N
477 H2NOC MS(FAB) m/z:
408([M+H]+) [Table 26]

A N
N ~ ~ Q
/N
Cl H p Q

N- 501 (HCI) Ex Q A Syn (Sal) 479 N ~/
Dat H2NOC MS(FAB) m/z:
427([M+H]+) 478 H2NOC /jN-p MS(FAB) m/z:
426([M+H]+) [Table 27]

A N ~
N \N p H pj ~J
Q

Ex Q p` Syn (Sal) H2N ~ N N _ F 501 (HCI) Dat 482 \/ MS(FAB) m/z:
433 ([M+H]+) H2NOC _ 234 (HCI) HNOC _ 501 (HCI) 480 ~ N ~ MS(FAB) m/z: 483 2 LN~~ \/ F MS(FAB) m/z:
415 ([M+H]+ ) 433 ([M+H]+) H2NOC~ F 501 (HCI) H2N ~~ 501 (HCI) 481 L N MS(FAB) m/z: 484 N N F MS(FAB) m/z:
433 ([M+H]+) 451 ([M+H]+) H2NOC F_ F 501 (HCI) H2NOC F_ 501 (HCI) L
485 LN ~ N MS(FAB) m/z: 496 N/ \/ MS(ESI) m/z:
451 ([M+H]+) 430 ([M+H]+) H NOC _ Br MS(ESI) 501 m/z: H2NOC _ 501 (HCI) 486 2 LN~N 497 LN / \/ F MS(ESI) m/z:
\ /
493 ([M+H]+) 430 ([M+H]+) H2NOC NC _ 501 (HCI) H2NOC Me0 _ 501 (HCI) 487 LN N MS(ESI) m/z: 498 LN C/ \/ MS(ESI) m/z:
440 ([M+H]+) 442 ([M+H] ) NC OMe H2NOC ~ _ 206 (HCI) 501 (HCI) 488 L~N \/ MS(FAB) m/z: 499 N I MS(ESI) m/z:
440 ([M+H]+) (442 ([M+H]+) H2NOC 501 (HCI) CONH 2 ~
489 N Np CN MS(ESI) m/z: H 2 NOC
L _ 501 (HCI) 440 ([M+H]+) 500 N \/ MS(ESI) m/z:
H2NOC NC F 501 (HCI) 414 ([M+H]+) 490 N N MS(ESI) m/z: N501 (HCI) 458 ([M+H]) 501 ~ MS(ESI) m/z:
501 (HCI) H2NOC 401 ([M+H]+) ~
491 <O~N rN MS(ESI) m/z: N501 (HCI) 440 ([M+H]) 502 1N-X)-F H NOC MS(ESI) m/z:
2 419 ([M+H]+) 492 p~N MS(FAB) m/z: H2NOC~ N_ 501 (HCI) 400 ([M+H]+) 503 LN N MS(FAB) m/z:
U
HO 501 416 ([M+H]+) 493 O~N MS(FAB) m/z: H2NOC N~ 501 (HCI) 403 ([M+H]+) 504 LN N\/ MS(ESI) m/z:
HO _ 501 446 ([M+H]+) 494 ~CN \/ HO MS(FAB) m/z: HO N _ 501 (HCI) 375 ([M+H]+) 505 L~N\/ MS(ESI) m/z:
H2N ~ 501 (HCI) OH 404 ([M+H]+) 495 N/ MS(ESI) m/z: N- 394 (HCI) 412 ([M+H]+) 506 /CN MS(ESI) m/z:
HO
374([M+H]+) N
N- F 234 (2HCI) HO N- 234 N
507 ~\-J MS(ESI) m/z: 517 )CN MS(ESI) m/z:
O NH2 434([M+H]+) CO2Me 432([M+H]+) N- 501 (2HCI) HO N- 36-167 (HCI) 508 ~N / MS(ESI) m/z: 518 O N \/ MS(ESI) m/z:
O NH2 413([M+H]+) NH2 417([M+H]+) F
N- 501 (HCI) O NH2 CN 529 (HCII
509 O N\/ MS(ESI) m/z: 519 ~N MS(FAB) m/z:
N H 2 419([M+H]+) 437([M+H]+) F 0 NH2 NC 234 (HCI) ~--~ N- 501 (2HCI) 510 ~~ MS(ESI) m/z: 520 N/ MS(FAB) m/z:
O NH2 434([M+H]+) 451([M+H]+) O NH- 2 \ CN F 501 (HCI) OrN NH2 F 234 (HCI) 511 \ N N MS(FAB) m/z: 521 O/ MS(FAB) m/z:
458([M+H]+) 430([M+H]+) O\ N H2 F NC 501 (HCI) S` 234 (HCI) 512 N N MS(FAB) m/z: 522 NN ~~ MS(FAB) m/z:
V 458([M+H]+) O N H2 421([M+H]+) p-~ C02Me NC 206 N ~ N 501 (2HCI) 513 ~ N\ MS(FAB) m/z: 523 N/\ MS(ESI) m/z:
N N HO 456([M+H]+) ~- ~ - 441([M+H]+) D 501 (HCI) 524 {JN/~ MS(ESI) m/z:
514 N MS(ESI) m/z: HO - 442([M+H]+) ~LN HZ 426([M+H]+) 501 (HCI) 525 N/\ MS(ESI) m/z:
515 N / - MS(FAB) m/z: HO - 428([M+H]+) ~N H2 426([M+H]+) 501 (HCI) 526 N C MS(ESI) m/z:
516 N MS(ESI) m/z: HO 441([M+H]+) p N CIP 2 428([M+H]+) O NH2 ~Me 501 O NH2 Me ~ N ~ ~ N,N 537 527 N N \ / N MS(ESI) m/z: 537 N N ~ MS(ESI) m/z:
Br 497[M+H]+) ~ 419([M+H]+) F CN 529 CO2Me NC 206 528 MS(ESI) m/z:
CO Et 538 MS(ESI) m/z:
2 448([M+H]+) 438([M+H]+) O~NH2 Br 529 NC
529 N~N ~\F MS(ESI) m/z: O NH2 N_ 501 + 539 ~N~N MS(ESI) m/z:
511 ([M+H]) O 455([M+H]+) 530 yN NMS(ESI) m/z: N-501 ~
v - F 458([M+H]+) 540 N~ MS(ESI) m/z:
CO2Me Br I~NH2 430([M+H]+) 531 N ~ \ MS(ESI) m/z:

509([M-H]-) F N 36 541 N / MS(ESI) m/z:
532 ~N / \ MS(FAB) m/z: 448([M+H]+) CO2H 420([M+H]+) 0 NH2 F

O NH2 N 167 542 N MS(ESI) m/z:
533 N _ MS(ESI) m/z: 448([M+H]+) F 419([M+H]+) Me Me~NH
e NH2 534 F N~\ MS(ESI) m/z: 543 C ~ N_ MS(ESI) m/z:
406([M+H]+) N 529([M+H]+) CO2Me Br 529 535 N MS(ESI) m/z: HN N 501 491([M+H]+) 544 0 MS(FAB) m/z:
386([M+H]+) 501 (HCI) O ~ N _ 501 536 ~ N MS(FAB) m/z: 545 H~N' ~` MS(FAB) m/z:
CONH 2 414([M+H]+) 387([M+H]+) Me -N\ e 546 N \/ MS(FAB) m/z: N Me 167 HO 404([M+H] ) 556 pj--CN \/ MS(FAB) m/z:
+
H O 501 486([M+H]+) -Me 547 Hp N\/ MS(FAB) m/z: N-Me 403([M+H]+) HNJ Me 167 501 557 -\~ N- MS(FAB) m/z:
548 MS(FAB) m/z: p 486([M+H]+) CO2Et 429([M+H]+) N-Me HO / \ 36 ~ `Me 167 549 p~~N - MS(FAB) m/z: 558 N N- MS(FAB) m/z:
401([M+H]+) O/~N \ / 498([M+H]+) CONH2 Me-0 501 0 - O
550 N\/N MS(ESI) m/z: I~-Me 431([M+H]+) 167 559 N N- MS(FAB) m/z:
CONH2 Ci 501 p;~N \/ 541([M+H]+) 551 N N MS(ESI) mlz:
435([M+H]+) ~---~ N - 501 N- 501 560 NU MS(ESI) m/z:
552 /CN \/ MS(FAB) m/z: Boc 459([M+H]+) CO2Et 430([M+H]+) ~ N- 146 (2HCI) O 36 561 H~ MS(ESI) m/z:
553 IN MS(FAB) m/z: 359([M+H]+) HO 402([M+H]+) N-Me ~Me ~ 167 N~ 562 N N- MS(ESI) m/z:
167 p~N 498([M+H]+) 554 TCN N_ MS(ESI) m/z: O 484([M+H]+) C>~ N * 167 N~Me r--/ Me 167 563 N N- MS(FAB) m/z:
~-C

-N \ ~
555 N N MS(FAB) m/z: 538([M+H]+) ~N \ ~ 472([M+H]+) O

CO2H 36 (N"IJ
167 (2HCI) 564 N N MS(ESI) m/z: 571 N MS(FAB) m/z:
~-CN- 513([M+H]+) OTCN 538([M+H]+) O

N-Me M~o 167 NMe 565 N N N- MS(ESI) m/z: 572 HN N- MS(ESI) m/z:
498([M+H]+) >/-CN
O 498([M+H]+) O

CN) Me 167 C501 N Np MS(FAB) m/z:
566 N_ MS(FAB) m/z:

~-CN 512([M+H]+) 457([M+H]+) 0 NH F3C ~ 501 H2N' 574 TN
167 \--/N y MS(FAB) m/z:
499([M+H]+) 567 HN N- MS(FAB) m/z:
/-CN 498([M+H]+) N - 501 0 575 ~/N Me MS(ESI) m/z:
p CO2Et 444([M+H]+) Ii 167 N -N /N__F 501 568 p N- MS(FAB) m/z: 576 MS(FAB) m/z:
N 471([M+H]+) CO2Et 448([M+H]+) ~Me 167 (2HCI) N 577 N Me MS(ESI) m/z:
569 , N- MS(ESI) m/z: CO2H 416([M+H]+) O UN 484([M+H]+) N N- F 36 578 / MS(ESI) m/z:
N CO2H 420([M+H]+) 167 (2HCI) 0 570 HN N- MS(FAB) m/z: * 167 (2HCI) N 478 M+H + 579 N MS(ESI) m/z:
~ ([ ] ) eNO Me 470([M+H]+) N ~ ~ * N
167 [ , * 167 580 Me, _ Me Me I~
N MS(ESI) m/z: 583 N F MS(ESI) m/z:
N~N \ ~ 588([M+H]+) O~N 592([M+H]+) O

N ~ / * Me N ~ 167 581 N MS(ESI) m/z:
N 588([M+H]+) / -ro Me O

N \ 167 582 Me ~ _ F MS(ESI) m/z:
N~ N
N \ / 592([M+H]+) [Table 28]

N N/aOH
H O

Q
Ex Q p` Syn (Sal) 501 (HCI) Dat H2NOC MS(ESI) m/z:
414 ([M+H]+) HZN ~ i--\ - 501 H2N ~ 501 584 N N \/ MS(FAB) m/z: 587 N/ MS(FAB) m/z:
429 ([M+H]+) 426 ([M+H]+) H2NL F _ 501 (HCI) 585 v MS(FAB) m/z:
447 ([M+H]+) [Table 29]

A ~ N
H r >- No O
N
Q

Ex Q A Syn (Sal) 590 CN ~ ~ 501 (ZHCf) Dat H2NOC MS(FAB) m/z:
399 ([M+H]+) H2NOC 501 (2HCI) 588 L UN MS(ESI) m/z:
413 ([M+H]+) H2NLC F 501 (2HCI) 589 N N MS(FAB) m/z:
431 ([M+H]+) [Table 30]
O
/~
N c ~~N~ Me Me H O
QT

H NOC F F
Ex Q A Syn (Sal) 2 Lr--\ - 501 (HCI) Dat 594 ~N MS(FAB) m/z:
453 ([M+H]+) HZNLC~ P 501 H2NOC _ 501 591 uMS(FAB) m/z: 595 N N CN
~ \ / MS(ESI) m/z:
417 ([M+H]+) 442 ([M+HI+) H2N~ ~ F 501 (HCI) H2N N 501 592 \-/ N \/ MS(FAB) m/z: 596 O~-C MS(FAB) m/z:
435 ([M+H]+) 402 ([M+H]+) H2NOC~ F_ 501 (HCI) H2N ~ - 501 (HCI) 593 LN ~N F MS(ESI) m/z: 597 N/ \/ F MS(FAB) m/z:
453 ([M+H]+) 432 ([M+H]+) OMe CONH2 F

598 501 (HCI) 608 ~ CN MS(ESI) m/z:
Ng' MS(FAB) m/z: 460([M+H]+) CONH 2 444 ([M+H]+) N-N 501 609 ~ U F MS(FAB) m/z:
599 /CN MS(FAB) m/z: CONH2 436([M+H]+) H2NOC 403 ([M+H +
] ) 501 (HCI) H2NOC N_ 501 (HCI) 610 ~N MS(FAB) m/z:
/~
600 Nv MS(FAB) m/z: CONH2 428([M+H]+) 418 ([M+H]+) N
N ~ \ F 501 H2NOC N e0 501 (HCI) 611 - MS(FAB) m/z:
601 N N\~ MS(FAB) m/z: CONH2 421([M+H]+) u 448 ([M+H]+) HO N 36-167 (HCI) 501 612 MS(ESI) m/z:
602 ~N F MS(FAB) m/z: CONH2 419([M+H]+) CON H2 434([M+H]+) OH N- 394 (HCI) 613 U - MS(ESI) m/z:
603 ~N / MS(ESI) m/z: 361([M+H]+) HO
406([M+H]+) CONH2 NC 501 N- 501 (2HCI) 614 LNN MS(ESI) m/z:
604 VN / MS(ESI) m/z: ~ 457([M+H]+) CON H2 415([M+H]+) ~ N- 501 (2HCI) CONH2 F 501 615 <N~ ~/ MS(ESI) m/z:
605 \N- MS(FAB) m/z: CONH2 432([M+H]+) 421([M+H]+) HN~ 501 ICO2 N- F 501 616 O N MS(ESI) m/z:
606 N N MS(ESI) m/z: 388([M+H]+) 436([M+H]+) O~ N - 501 C NH CN 617 HN~ MS(ESI) m/z:
2 501 ]+) 607 ~N N F MS(ESI) m/z: 389([M+H
460([M+H]+) HO - 501 618 N \ ~ MS(ESI) m/z:
HO 405([M+H]+) 0 N N\ 723 C0Me 36 619 _ MS(FAB) m/z: 622 ~/ MS(ESI) m/z:
362([M+H]+) 433([M+H]+) C02Et Me 620 kN-IY MS(ESI) m/z: 623 N\~ CI MS(ESI) m/z:
461([M+H]+) CO2H 437([M+H]+) 621 N~~ C~ MS(ESI) m/z: 624 ~CN MS(API) m/z:
CO2Et 465([M+H]+) CO2Me 434([M+H]+) [Table 31]

N N RI
Q O
N H IS
~
CN
I
Me Ex Rl Syn (Sal) HO 691 (HCI) Dat 630 o MS(FAB) m/z:

501 (HCI) 395 ([M+H]+) F
625 MS(FAB) m/z: MeO 501 (HCI) 397 ([M+H]+) 631 MS(FAB) m/z:
CI 501 (HCI) 409 ([M+H]+) 626 MS(FAB) m/z: OMe 501 (HCI) 413 ([M+H]+) 632 6 MS(FAB) m/z:
CI 501 (HCI) 409 ([M+H]+) 627 MS(FAB) m/z: NMe2 662 (2HCI) 413 ([M+H]+) 633 MS(FAB) m/z:
Br 501 422 ([M+H]+) 628 MS(FAB) m/z: NMe2 (2HCI) ) 634 2 MS(FAB) m/z:
457 ([M+H]+
Br 501 422 ([M+H]+) 629 MS(FAB) m/z:
457 ([M+H]+) HOLO C 635 (HCI) 146 (2HCI) 635 MS(ESI) m/z: 641 -CINH MS(ESI) m/z:
423 ([M+H]+) 386([M+H]+) CONH2 167 (HCI) Me 28 (HCI) 636 MS(FAB) m/z: 642 N-~\ MS(FAB) m/z:
422 ([M+H]+) 0 428([M+H]+) N 501 (2HCI) 793 (2HCI) 637 MS(FAB) m/z: 643 -CN-Me MS(ESI) m/z:
380 ([M+H]+) 400([M+H]+) N- 501 (3HCI) 0 31 (HCI) 638 MS(FAB) m/z: _ 644 N-S Me MS(FAB) m/z:
380 ([M+H]+) O 464([M+H]+) 501 (2HCI) 639 - ~N-Me MS(FAB) m/z: ~_~ 2~
415 ([M+H]+) 645 ~N MS(FAB) m/z:
501 0 490([M+H]+) 640 --CN-Boc MS(FAB) m/z:
486([M+H]+) [Table 32]

N
N ,rRl ~N) H ~
S
O N
H

N 501 (2HCI) Ex Rl Syn (Sal) 647 MS(FAB) m/z:
Dat 380 ([M+H]+) F 501 ~ O 501 646 MS(FAB) m/z: 648 MS(ESI) m/z:
397 ([M+H]+) 369 ([M+H]+) [Table 33]

N
N H
N S
CO2Et Ex R~ Syn (Sal) _N3 501 Dat 650 MS(FAB) m/z:
N 501 429 ([M+H]+) 649 MS(FAB) m/z:
437 ([M+H]+) [Table 34]

N IN
H
N S
COZH

Ex Rl Syn (Sal) _N/ 36 (Na) Dat 652 MS(FAB) m/z:
N 36 (Na) 401 ([M+H]+) 651 MS(FAB) m/z:
409 ([M+H]+) [Table 35]

O
(?-N N\rR1 H~
N S

Ex RI Syn (Sal) -N+_O 501 Dat 661 MS(ESI) m/z:
\ / 424 ([M+H]+) -N 501 (HCI) 653 MS(FAB) m/z: OII 662 408 ([M+H]+) 662 ~ MS(FAB) m/z:
==N 501 397 ([M+H]+) 654 MS(FAB) m/z: O 501 N 409 ([M+H]+) 663 ~~ MS(FAB) m/z:
-N 501 (HCI) 397 ([M+H]+) 655 ~N MS(ESI) m/z: 664 409 ([M+H]+) 664 _ND MS(FAB) m/z:
N OMe 692 400 ([M+H]+) 656 MS(FAB) m/z: 501 438 ([M+H]+) 665 -N~OH MS(ESI) m/z:
CI N 662 444 ([M+H]+) 657 j MS(FAB) m/z: N 501 442 ([M+H]+) 666 - ~OEt MS(ESI) m/z:
HO -N 501 486([M+H]+) 658 j MS(FAB) m/z: O 36 Na 424 ([M+H]+) 667 -N~~OH MS(FAB) m/z:
MeO N 692 458 ([M+H]+) 659 MS(FAB) m/z: _N S 234 (HCI) 438 ([M+H]+) 668 ~ MS(FAB) m/z:
C\/N-o + - 501 432 ([M+H]+) 660 MS(ESI) m/z: /-\_O 76 424 ([M+H]+) 669 -N~ MS(FAB) m/z:
448 ([M+H]+) `-~ 0 723 Me 234 670 -NS,'p MS(FAB) m/z: 678 MS(FAB) m/z:
464 ([M+H]+) 429([M+H]+) 671 __N~` H MS(FAB) m/z: 679 O MS(FAB) m/z:
429 ([M+H]+) 415([M+H]+) N ~ 234 672 -'N\--i Me MS(FAB) m/z: 680 MS(ESI) m/z:
457 ((M+HI+) 399([M+H]+) Me 234 673 - NOMe MS(FAB) m/z: 681 -~ MS(ESI) m/z:
471 ([M+H]+) Me 373([M+H]+) N a-z 234 MS(FAB) m/z: 682 S MS(ESI) m/z:
422 ([M+H]+) H N 501 (HCI) 431([M+H]+) N ~ 234 675 ~/ MS(FAB) m/z: p 423 ([M+H]+) 683 ---C ~ MS(FAB) m/z:
401([M+H]+) 676 Me MS(FAB) m/z: 356 (HCI) 387([M+H]+) 684 -N~ H MS(FAB) m/z:
234 415([M+H]+) M e 677 MS(FAB) m/z:
Me 401([M+H]+) [Table 36]

Q O

'S
CN ) H
N
~CONH2 Ex Rl Syn (Sal) N 693 (2HCI) Dat 693 MS(ESI) m/z:
501 (2HCI) NH2 438 ([M+H]+) 685 N~ MS(FAB) m/z: 850 (2HCI) 424 ([M+H]+) 694 MS(ESI) m/z:
N 501 (HCI) NHMe 452 ([M+H]+) 686 N~ MS(FAB) m/z: - 695 (2HCI) 424 ([M+H]+) 695 ~~N MS(ESI) m/z:
-N) 501 (HCI) NMe2 466 ([M+H]+) 687 N MS(ESI) m/z: Q'\-/ 69 5 (2HCI) 424 ([M+H]+) 696 N~OMe MS(ESI) m/z:
_N+O 501 (HCI) Me 510 ([M+H]+) 688 MS(ESI) m/z: 206 (HCI) 439 ([M+H]+) 697 MS(ESI) m/z:
Cl\- O Me 501 CN 448 ([M+H]+) 689 N MS(FAB) m/z:
453 ([M+H]+) 698 (HCI) 698 Q\/N MS(ESI) m/z:
N 501 (HCI) CONH2 MS(FAB) m/z: 466 ([M+H]+) CI 457 ([M+H]+) O 501 (HCI) 699 --~~ MS(FAB) m/z:
691 691 (HCI) MS(ESI) m/z: 412 ([M+H]+) OH 439 ([M+H]+) 700 O 501 (HCI) MS(FAB) m/z:
692 412 ([M+H]+) 692 MS(ESI) m/z:
356 (HCI) OMe 453 ([M+H]+) 701 -N F MS(ESI) m/z:
447 ([M+H]+) 356 (HCI) OH 501 (HCI) 702 -N~ MS(FAB) m/z: 713 N~OH MS(ESI) m/z:
F 447 ([M+H]+) 475 ([M+H]+) _N~O 703 (HCI) * 356 (HCI) 703 MS(ESI) m/z: 714 N,.., OH MS(FAB) m/z:
443 ([M+H]+) 445 ([M+H]+) OH 501 (HCI) ~C 356 (HCI) 704 __N ~[c MS(ESI) m/z: 715 N JOH MS(ESI) m/z:
445 ([M+H]+) 445 ([M+H]+) * OH 501 (HCI) N * 356 (HCI) 705 _No MS(ESI) m/z: 716 N OMe MS(FAB) m/z:
445 ([M+H]+) 459 ([M+H]+) 356 (HCI) * 356 (HCI) _NaOMe 706 MS(ESI) m/z: 717 N OMe MS(FAB) m/z:
459 ([M+H]+) ~ 459 ([M+H]+) _N~CONH2 501 (2HCI) 718 (HCI) 707 MS(ESI) m/z: 718 -N~ MS(ESI) m/z:
472 ([M+H]+) 401 ([M+H]+) O~ OH 501 (2HCI) - NOH 356 708 N~H MS(FAB) m/z: 719 MS(ESI) m/z:
530 ([M+H]+) 417 ([M+H]+) O O 501 (2HCI) ~ 356 (HCI) 709 -N~N MS(FAB) m/z: 720 -NO MS(FAB) m/z:
H 556 ([M+H]+) 445 ([M+H]+) _ND 356 (HCI) ~OMe 356 (HCI) 710 MS(FAB) m/z: 721 _N O MS(FAB) m/z:
415 ([M+H]+) 475 ([M+H]+) OH ~k 356 (HCI) 234 (HCI) 711 -Na MS(ESI) m/z: 722 -"Ns MS(FAB) m/z:
OH 447 ([M+H]+) 447 ([M+H]+) ,OH 501 (2HCI) _N S_O 723 (HCI) 712 N MS(ESI) m/z: 723 \J MS(ESI) m/z:
~'OH
447 ([M+H]+) 463 ([M+H]+) ~--~ O 723 ~ Me 356 (HCI) 724 -N~ ~ MS(FAB) m/z: 735 N MS(ESI) m/z:
479 ([M+H]+) OH 419 ([M+H]+) f--\ NH 356 (2HCI) N H 356 (HCI) 725 -N~/ MS(FAB) m/z: 736 ~OH MS(ESI) m/z:
430 ([M+H]+) 405 ([M+H]+) O 501 (HCI) N11 Et 356 (HCI) 726 MS(ESI) m/z: 737 OMe MS(FAB) m/z:
444 ([M+H]+) 447 ([M+H]+) O 356 (HCI) r-"Me 356 (HCI) 727 -N \--/ NH MS(ESI) m/z: 738 ~N-/`OMe MS(ESI) m/z:
458 ([M+H]+) 461 ([M+H]+) _N 501 MeYMe 501 (HCI) 728 ~Boc MS(ESI) m/z: 739 MS(ESI) m/z:
461 ([M+H]+) OMe 461 ([M+H]+) -NH 146 501 (HCI) 729 2 MS(ESI) m/z: 740 -N MS(FAB) m/z:
361 ([M+H]+) OMe 473 ([M+H]+) /Me 356 (HCI) 730 -N~Me MS(FAB) m/z: ~CF3 501 (HCI) 389 ([M+H]+) 741 -N MS(FAB) m/z:
~Me 356 (HCI) OMe 501 ([M+H]+) 731 ,N MS(ESI) m/z: ~OMe 356 (HCI) 429 ([M+H]+) 742 NOMe MS(FAB) m/z:
H 356 (HCI) 477 ([M+H]+) 732 NF MS(FAB) m/z: Me OMe 356 (HCI) 407 ([M+H]+) 743 MS(FAB) m/z:
H 356 (HCI) 447 ([M+H]+) 733 ,N~CF3 MS(FAB) m/z: NMe 356 (HCI) 457 ([M+H]+) 744 , ~O MS(ESI) m/z:
CI 734 (HCI) Me 445 ([M+H]+) H
734 -N MS(ESI) m/z: ~ 356 (HCI) 437 ([M+H]+) 745 MS(ESI) m/z:
0 459 ([M+H]+) Me 146 (2HCI) Me 356 (HCI) 746 MS(FAB) MS(FAB) m/z: 757 N MS(ESI) m/z:
2 418 ([M+H]+) 465 ([M+H]+) Me 356 (2HCI) Me 356 (HCI) 747 oN~NMe MS(FAB) m/z: 758 -N MS(FAB) m/z:
2 446 ([M+H]+) u 455 ([M+H]+) Me 28 (HCI) Me 356 (2HCI) 748 ~N`iNHAc MS(FAB) m/z: 759 ,N MS(ESI) m/z:
\~/1\ ~
460 ([M+H]+) 480 ([M+H]+) Me 31 (HCI) 501 749 NHMs MS(FAB) m/z: 760 -Br MS(ESI) m/z:
496 ([M+H]+) 426 ([M+H]+) Me 356 146 (2HCI) 750 N~NHBoc MS(FAB) m/z: 761 N MS(FAB) m/z:
518 ([M+H]+) ~~~/// 429([M+H]+) Me., Ph 356 p 28 (2HCi) 751 ~ Ph MS(FAB) m/z: 762 --CN4 MS(FAB) m/z:
596 ([M+H]+) Me 471([M+H]+) Me 356 (HCI) 185 752 N~~ MS(FAB) m/z: 763 OH MS(FAB) m/z:
CN 428 ([M+H]+) 487(IM+HI+) Me 356 (HCI) Me 234 (HCI) 753 eN~CO2Me MS(FAB) m/z: 764 MS(FAB) m/z:
447 ([M+H]+) 1Me 416([M+H]+) Me 36 (HCI) 234 (HCI) 754 IIN~CO2H MS(FAB) m/z: 765 Me MS(FAB) m/z:
433 ([M+H]+) 444([M+H]+) Me 356 (HCI) 234 (HCI) 755 sN,---ICONH2 MS(FAB) m/z: 766 O MS(FAB) m/z:
432 ([M+H]+) 430([M+H]+) Me 356 (HCI) 234 (HCI) 756 -N~CONMe2 MS(FAB) m/z: ~
767 ~ MS(FAB) m/z:
460 ([M+H]+) 416([M+H]+) 234 (HCI) 501 (HCI) 768 MS(ESI) m/z: 779 OH MS(ESI) m/z:
414([M+H]+) 404([M+H]+) Me 234 (HCI) 501 (HCI) 769 --~ MS(ESI) m/z: 780 Me MS(FAB) m/z:
Me 388([M+H]+) 418([M+H]+) 0 28 (HCI) Me 501 (HCI) 770 N-J~ Me MS(FAB) m/z: 781 MS(FAB) m/z:
471([M+H]+) OH 390([M+H]+) Me 234 (HCI) Me 501 (HCI) 771 MS(FAB) m/z: 782 -1 MS(FAB) m/z:
402([M+H]+) 0 388([M+H]+) 146 (2HCI) Me 501 (HCI) 772 MS(FAB) m/z: 783 MS(FAB) m/z:
429([M+H]+) 0-Me 404([M+H]+) BeC 501 501 (HCI) 773 MS(FAB) m/z: 784 _N O-Me MS(FAB) m/z:
529([M+H]+) \-j 459([M+H]+) 234 (HCI) ,Me 356 (2HCI) 774 S MS(ESI) m/z: 785 NN~Me MS(FAB) m/z:
446([M+H]+) H 432([M+H]+) 0 723 (HCI) 356 (2HCI) 775 O MS(ESI) m/z: 786 N N-Me MS(FAB) m/z:
478([M+H]+) \-j 444([M+H]+) 234 (HCI) NMe 356 (HCI) 776 Me MS(FAB) m/z: 787 ~ MS(FAB) m/z:
374([M+H]+) O 459([M+H]+) O 185 (2HCI) /Me 356 (2HCI) 777 H2N 486([M+H],) z. 788 -N /N MS(FAB) m/z:
466([M+H]+) O 9~ 356 (HCI) 778 N4 MS(ESI) m/z: 789 -N~~OH MS(ESI) m/z:
NH2 +
472([M+H] ) 445([M+H]+) 356 (HCI) Me Me 501 (HCI) 790 -N MS(ESI) m/z: 801 OH MS(FAB) m/z:
Me * 429([M+H]+) 418([M+H]+) Me Me 501 (HCI) -N 356 (HCI) 802 ~O~ MS(FAB) m/z:
~ MS I z:
791 (ES ) m/ Me 432(LM+HI+) Me * 429([M+H]+) Me Me 356 (HCI) 0-Me 792 (HCI) 803 -N o~O MS(FAB) m/z:
792 p, MS(FAB) m/z: 477([M+H]+) 420([M+H]+) Me Me 662 (HCI) i Me 793 (2HCI) 804 --N MS(ESI) mlz:
793 N N/~ MS(FAB) m/z: \-~ p 465([M+H]+) 472(LM+HI+) Me o Me 662 (HCI) O MS(ESI) m/z:
Me OH 356 (HCI) 805 _N S,, 794 N MS(ESI) m/z: \ 481([M+H]+) 433([M+H]+) 501 (2HCI) Me O--\ 356 (HCI) 806 MS(ESI) m/z:
795 Me MS(FAB) m/z: ~ 445([M+H]+) 447 M+H +
(L ] ) Me M ; 501 (2HCI) Me S-Me 356 (HCI) 807 N p MS(FAB) m/z:
796 MS(FAB) m/z: 447([M+H]+) 449([M+H]+) 501 (HCI) 356 (HCI) 808 O MS(ESI) m/z:
797 -N F MS(ESI) m/z: N-N Me 454([M+H]+) F 465([M+H]+) Me 501 (HCI) F 356 (HCI) 809 ~OH MS(ESI) m/z:
798 N MS(ESI) mlz: 418([M+H]+) D<F 451([M+H]+) Me ~
N ~ , 356 (HCI) * 356 (HCI) 810 -' ~ MS(ESI) m/z:
799 -N MS(ESI) m/z:
([M+H]+) F 433([M+H]+) ~p 578 356 (HCI) N
* e 356 (2HCI) 800 -N~ MS(ESI) m/z: 811 N p Me MS(ESI) m/z:
F 433([M+H]+) 488([M+H]+) - 356 (HCI) /--\_Me 356 (2HCI) 812 N Me MS(ESI) m/z: 823 -N N MS(FAB) m/z:
* 0 445([M+H]+) 458([M+H]+) O 356 Me 356 813 N~ Me MS(FAB) m/z: 824 /N MS(ESI) m/z:
431([M+H]+) ~O 431([M+H]+) 814 -N~OH MS(ESI) m/z: 825 /N---oO MS(ESI) mlz:
431([M+H]+) 417([M+H]+) O'Me 815 (2HCI) /--Me 356 (HCI) 815 MS(FAB) m/z: 826 -N MS(ESI) m/z:
~NH ~k 474([M+H]+) \-Me 417([M+H]+) Me 501 (HCI) 815 (2HCI) 816 --~j-Me MS(FAB) m/z: 827 -NNH MS(FAB) m/z:
432([M+H]+) =,OH 460([M+H]+) Me Me 501 (HCI) \H
817 O~ MS(FAB) m/z: ~ 356 (2HCI) Me 446([M+H]+) 828 MS(FAB) m/z:
Me 146 (2HCI) V::N 442([M+H]+) 818 ON MS(FAB) m/z: ~C 474([M+H]+) /\O 501 (HCI) 829 ~N_)~ MS(ESI) m/z:
Me Me 501 (HCI) OH 461([M+H]+) 819 H MS(FAB) m/z:
432([M+H]+) O, Me 356 (HCI) 830 -N~J MS(ESI) m/z:
Me OH 662 (HCI) O-Me 475([M+H]+) 820 ~N 1 MS(ESI) m/z: 501 (HCI) Me 433([M+H]+) o 831 N~ Me MS(ESI) m/z:
H Ol Me 821 O 475([M+H]+) 821 ~,N MS(ESI) m/z: 146 (2HCI) O-'Me 477([M+H]+) 832 Me N H MS(FAB) m/z:
[---'NH 356 (2HCI) 443([M+H]+) 822 MS(FAB) m/z:
444([M+H]+) ~t f-CF3 662 (HCI) Ci 723 (HCI) 833 /N MS(FAB) m/z: 842 MS(FAB) m/z:
0 513([M+H]+) CI 504([M+H]+) Br 723 (HCI) 356 834 O\/ MS(FAB) m/z: 843 _N MS(ESI) m/z:
530([M+H]+) Q OH 521([M+H]+) ,Me 835 (2HCI) 0 501 (HCI) 835 N MS(ESI) m/z:
~NH + 844 N MS(ESI) m/z:
444([M H]+) 429([M+H]+) Me 793 (2HCI) 501 836 /N N'Me MS(ESI) m/z: N-BoC
~/ 845 ~ MS(ESI) m/z:
v 458 M+H +
([ ] ) 529([M+H]+) Me 837 (2HCI) 0 501 837 MS(ESI) m/z:
N 846 ) MS(ESI) m/z:
H 444([M+H]+) N
\BoC 515([M+H]+) CF 723 (HCI) 838 ~\ 3 MS(FAB) m/z: O'Me 501 847 * ~ MS(FAB) m/z:
504(LM+HI+) _NN -BOC 574 [M+H
Me 356 (HCI) ( ]+) 839 -N ~ MS(ESI) m/z: \,~ 356 459([M+H]+) 848 N N MS(FAB) m/z:
OH 723 ~C =-OH 550([M+H]+) 840 -N~ MS(ESI) m/z: Me * CH 461([M+H]+) 849 N-BoC MS(FAB) m/z:
Me 723 (2HCI) 543([M+H]+) 841 /\N MS(FAB) mlz:
Me 403([M+H]+) [Table 37]

N
N ,~ Ex R' Syn (Sal) H ~ S R Dat N 850 (2HCI) 850 ~ ~ MS(ESI) m/z:
Me O H' NHMe 466 ([M+H]+) [Table 38]

N ~
N H I S R

Ex RI Syn (Sal) Me 501 (HCI) Dat 856 MS(FAB) m/z:
0 374([M+H]+) 501 (HCI) 851 MS(FAB) m/z: Me 501 (HCI) ,/N-,-'-OMe 459 ([M+H]+) 857 MS(FAB) m/z:
501 (HCI) 0-Me 390([M+H]+) 852 -cO MS(ESI) m/z: 501 (HCI) 416([M+H]+) 858 MS(FAB) m/z:
O-Me 501 (HCI) -N\-"1 Me 445([M+H]+) 853 MS(ESI) m/z: Me OH 662 (HCI) Me 374([M+H]+) 859 -N~ MS(ESI) m/z:
501 (HCI) Me 419([M+H]+) 854 _~--~ Me MS(FAB) m/z: Me 0-Me 234 (HCI) 404([M+H]+) 860 N MS(FAB) m/z:
Me 433([M+H]+) Me 501 (HCI) 855 MS(ESI) m/z:
OH 376([M+H]+) [Table 39]

O

H ' O
N
CN) `CONH2 Ex Ri Syn (Sal) HO 501 (HCI) Dat 869 MS(FAB) m/z:
436([M+H]+) S 501 (HCI) 861 MS(ESI) m/z: 501 (2HCI) 412([M+H]+) 870 MS(ESI) m/z:
0 501 (HCI) 489([M+H]+) 862 MS(FAB) m/z: _ O 146 (2HCI) 396([M+H]+) 871 N MS(ESI) m/z:
0 501 (HCI) H 415([M+H]+) 863 MS(FAB) m/z: 723 (HCI) 396 [M+H + *
( l) 872 N~ MS(ESI) m/z:
N 864 Me 441([M+H]+) 864 MS(ESI) m/z: Br 501 (HCI) 395([M+H]+) 873 O 0 MS(FAB) m/z:
501 (HCI) 514([M+H]+) 865 -cO MS(ESI) m/z:
414([M+H]+) Me 723 (HCI) 874 O~ MS(FAB) m/z:
501 (HCI) M e 402([M+H]+) 866 --C)--OH MS(ESI) m/z: 723 (HCI) 428([M+H]+) 875 D--Me MS(FAB) mlz:
OH 501 (HCI) 374([M+H]+) 867 MS(ESI) m/z:

428([M+H]+) 876 MS(ESI) m/z:
,,.
S 501 (HCI) 428([M+H]+) 868 MS(ESI) m/z:
412([M+H]+) [Table 40]

I i N Ex R~ Syn DtSal) ONi-R1 a 877 GN~ M S(ESI) m/z:
CONH2 440 ([M+H]+) [Table 41]

(;~N 0 Ex R2 Syn (Sal) N - Dat H ~ 1 \ /
(N) 2 S Br~ 501 (HCI) N R 878 MS(FAB) m/z:
502 ([M+H]+) ~CONH2 ~
N 501 (HCI) 879 G MS(FAB) m/z:
491 ([M+H]+) [Table 42]

H SY R
CN ) N
N
~-CONH2 Ex RI Syn (Sal) Me 356 (HCI) Dat 882 ~OMe MS(FAB) m/z:
-Br 501 433 ([M+H]+) 880 MS(FAB) m/z: CF3 723 (HCI) 424 ([M+H]+) 883 ~ i MS(FAB) mlz:
_N ~ 356 (HCI) 504([M+H]+) 881 \--J MS(FAB) m/z:
431 ([M+H]+) [Table 43]

A
N S O
HC
QT

Q A Syn (Sal) N N 501 (HCI) Ex Dat 892 \ i MS(ESI) m/z:
CON H
2 416([M+H]+) p 146 (HCI) 501 (HCI) 884 HN / MS(FAB) m/z: 893 N N MS(FAB) ~ ~ \ / m/z:
370([M+H]+) CON H2 444([M+H]+) 501 N _ 885 N / \/ MS(FAB) m/z: N N 501 (2HCI) BoC 185 470([M+H]+) 894 ~-j \/ MS(FAB) m/z:
CON H2 431([M+H]+) (HCI) 886 FN P!--P MS(ESI) m/z: 501 (HCI) CO2 427([M+H]+) 895 N/ F MS(FAB) m/z:
234 (HCI) CONH2 434([M+H]+) 887 MS(FAB) m/z: Me, 0 CONH N_ 501 (HCI) 2 429([M+H]+) 896 N~ N\/ MS(FAB) m/z:
6H~ CONH 461([M+H]+) 888 FN / \ / MS(FAB) m/z: 2 CN 409([M+H]+) NC 501 (HCI) F_ 501 897 VNu MS(ESI) m/z:
889 ~N vN MS(ESI) m/z: CONH2 455([M+H]+) CON H2 448([M+H]+) N//-O
F rN 501 (HCI) ~~ - 501 (HCI) 898 N/'-~ MS
(ESI) m/z:
890 ~ v MS(ESI) m/z: N :5D
455([M+H]+) CON H2 448([M+H]+) /~~ - 501 (HCI) Me\ - O 501 (HCI) 891 U F MS(ESI) m/z: 899 VN MS(ESI) m/z:
CON H2 448([M+H]+) CON H2 457([M+H]+) [Table 44]

A N Me N
~
H
Me a NC
Ex Q p` Syn (Sal) ~ - 501 (HCI) Dat 905 (~ ~N MS(FAB) m/z:
ICON CONH2 413([M+H]+) \ - 501 (HCI) 900 ~ N \~ MS(FAB) m/z: N~ N
CONH Y' 501 (HCI) 2 385([M+H]+) 906 MS(FAB) m/z:
- 501 (HCI) 413([M+H]+) 901 ~N \ / MS(FAB) m/z:
CONH2 387([M+H]+) CONH2 F 501 (HCI) N-501 (HCI) 907 \N-j MS(FAB) m/z:
902 N\ iN MS(ESI) m/z: 392([M+H]+) CON H2 374([M+H]+) F
/-~ pN-/ 501 (2HCI) N N- 501 (2HCI) 908 ~ UN MS(FAB) m/z:
903 ~\-~ MS(FAB) m/z: CONH2 407([M+H]+) CONH2 389([M+H]+) ~~ N - 501 (2HCI) N- 501 (HCI) 909 F U \/ F MS(FAB) m/z:
904 N F MS(FAB) m/z: CONH2 407([M+H]+) CONH2 392([M+H]+) [Table 45]

A ~ N
N I ~N~ O/Me HC
S
Q

Ex Q p` Syn (Sal) /CN - M O 36 Dat 918 MS(ESI) m/z:
CO2H 461([M+H]+) 910 'CN MS(ESI) m/z: N\/ CI
HO 919 ~ MS(ESI) m/z:
434([M+H]+) C02H 465([M+H]+) 911 LN1F MS(ESI) m/z: CONH O 501 460([M+H]+) 920 ~N 2 MS(FAB) m/z:
487([M+H]+) CONH2 CN_ 723 N~
912 LN N\/ MS(ESI) m/z: /--\ - 501 470([M+H]+) 921 501 ` 2 N \/ 0 MS(FAB) m/z:
N /\ F CONH CF3 529([M+H]+) 913 - MS(FAB) m/z: Br Me, C02Et 477([M+H]+) /~ - O 501 922 ~N~ MS(FAB) m/z:
36 553([M+H]+) 914 ~jN /\ F MS(FAB) m/z: CONH2 COZH 449([M+H]+) Me, N N- F 501 923 ~ N~ NMS(FAB) m/z:
915 1 / CONH MS(FAB) m/z: CON H2 475([M+H]+) 2 449([M+H]+) CN Me Me 206 924 f-N~ MS(ESI) m/z:
MS(ES
) m/z:
916 /7N_cO / N 500 M+H +
CO Et CO H ([ ] ) 2 489([M+H]+) 2 917 N\/ CI MS(ESI) m/z:
CO2Et 493([M+H]+) [Table 46]

A N
N \- N~,, S F
H Cj Q *

N-Ex Q A Syn (Sal) N F 501 Dat 930 /0 ~ ~ MS(FAB) m/z:
CON H2 437([M+H]+) HO 234-36 Me 925 N -167 (HCI) 931 N~ O MS(ESI) m/z:
CONH2 MS(ESI) m/z: C02Et 477([M+H]+) 435([M+H]+) HO N- 234 (HCI) N CI 356 926 NMS(ESI) m/z: 932 MS(ESI) m/z:
OH 422([M+H]+) CO2Et 481([M+H]+) CN Me /--\ 723 - ~O 36 927 ~ v _ MS(ESI) m/z: 933 NMS(ESI) m/z:
CONH2 458([M+H]+) CO2H 449([M+H]+) N ~ F 501 - 36 928 MS(FAB) m/z: 934 N ~~ CI MS(ESI) m/z:
C02Et 465([M+H]+) C02H 453([M+H]+) 929 MS(FAB) m/z:
CO2H 437([M+H]+) [Table 47]
O
A N

H I EDs ~N`~O\Me Q

p` Syn (Sal) - M O 501 Ex Dat 938 ~jN\ / MS(ESI) m/z:
CO2Et 475([M+H]+) CN
N /\ 723 - Me 935 ~~ - MS(ESI) m/z: 939 /'NO \~ MS(ESI) m/z.
ICON H2 456([M+H]+) CO2H 447([M+H]+) 1N_-----F N- 501 /N--CI 36 936 \/ MS(FAB) m/z: 940 \/ MS(ESI) m/z:
CONH2 435([M+H]+) CO2H 452([M+H]+) 937 N~~ CI MS(ESI) m/z:
CO2Et 479([M+H]+) [Table 48]

A
N O o HC
Q

501 (HCI) Ex Q p` Syn (Sal) N N - F
Dat 942 ~ U MS(ESI) m/z:
CONH2 432([M+H]+) N 501 (HCI) CO~ F F 501 (HCI) 941 MS(ESI) m/z: 943 LN N MS(ESI) m/z:
CONH2 400([M+H]+) ~--~ -450([M+H]+) [Table 49]

A N Ex Q A Syn (Sal) N c Dat 944 /N- MS(ESI) m/z:
CON H2 357([M+H]+) [Table 50]
F
O
N. N N R1 H ' Ex RI Syn (Sal) Me 356 Dat 948 iN MS(FAB) m/z:
501 449([M+H +
]) 945 -NO-O~Me MS(FAB) m/z:

463([M+H]+) 949 --Br MS(FAB) m/z:
N 501 428([M+H]+) 946 MS(FAB) m/z:
Me * 433([M+H]+) r Me 356 947 -.N~ , Me MS(FAB) m/z:
451([M+H]+) [Table 51]

N. N R

Syn (Sal) 952 ~
Ex R Dat 952 -N O Me MS(ESI) m/z:
501 (HCI) 443([M+H]+) 950 QH MS(ESI) m/z:
414([M+H]+) OH 501 (HCI) 951 MS(ESI) m/z:
414([M+H]+) [Table 52]
F

H 11-~N
YR
C02Et Ex R' Syn (Sal) ' Me 501 Dat 955 N O Me MS(FAB) m/z:
f'O * 501 Me * 479([M+H]+) 953 iNJ Me MS(FAB) m/z: _N--Me 501 = O' 507([M+H]+) 956 Me MS(FAB) m/z:
501 Me ~k 479([M+H]+) -N
-N O
954 MS(FAB) m/z: 501 * 957 MS(FAB) m/z:
Me` 477([M+H]+) 475([M+H]+) 501 Me Me 501 958 N MS(FAB) m/z: 959 --N~ Me MS(FAB) m/z:
O.Me 491([M+H]+) /\O' 493([M+H]+) [Table 53]
F
O

N H

Ex R~ Syn (Sal) _N~-M O 36 Dat 963 -Me MS(FAB) m/z:
ro 36 Me ~k 451([M+H]+) *
960 Me MS(FAB) m/z: 36 479([M+H]+) 964 -N MS(FAB) m/z:
O
447([M+H]+) 36 ~t 36 _ N 0 961 MS(FAB) m/z: 965 -N MS(FAB) m/z:
Me` * 449([M+H]+) ',O-Me 463([M+H]+) Me 36 Me 36 /
962 -N O`Me MS(FAB) m/z: 966 _-NMe Me MS(FAB) m/z:
Me * 451([M+H]+) O 465([M+H]+) [Table 54]

~ 0 Syn (Sal) F ~ H ~ N,~_. Rl Ex R' Dat N 0-Me 501 (HCI) CN S
~CONH2 967 S-~ MS(FAB) m/z:
436([M+H]+) [Table 55]

Syn (Sal) N H ~ N s ,r RI Ex R1 Dat Me 36 (HCI) _N 0-Me MS(FAB) m/z:
Z

Me 449([M+H]+) [Table 56]

~ O
NC ~ N N. 1 Ex R1 Syn (Sal) N H ~ R Dat C ' Me 723 N
~-CONH2 969 N~O MS(ESI) m/z:
470([M+H]+) _. N 723 970 MS(ESI) m/z:
Me\*' * 454([M+H]+) [Table 57]

A N
N ~ -N OH
H S

Q

Q A Syn (Sal) /CN Ci 356 Ex Dat 972 MS(ESI) m/z:
CO2Et 507([M+H]+) Me 356 Me 971 /N-(1I--0 MS(ESI) m/z: 973 /N-c--/ O MS(ESI) m/z:
CO2Et 503([M+H]+) CO2H 475([M+H]+) 974 N ~~ CI MS(ESI) m/z:
CO2H 479([M+H]+) [Table 58]

A N Ex Q A Syn (Sal) N c ~>--BC Dat H s ~ 975 N~~ C' MS(ESI) m/z:
CO2Et 472([M+H]+) _ Me 501 976 /N_$_0 MS(FAB) mlz:
CO2Et 468([M+H]+) [Table 59]

Syn (Sal) N H T N,~R Ex R1 S Dat Me 234 977 -N 0-Me MS(ESI) mlz:
HO CO2Me Me 464([M+H]+) [Table 60]

H CN ) ~_R

O
Ex R1 Syn (Sal) --C N 980 Dat 979 MS(ESI) m/z:
980 367 ([M+H]+) 978 $ MS(ESI) m/z:
372 ([M+H]+) [Table 61]

N H
Os Ex Rl Syn (Sal) Ci 980 Dat 984 MS(ESI) m/z:
980 398 ([M+H]+) 980 MS(ESI) m/z: 980 364 ([M+H]+) 985 S' MS(ESI) m/z:
980 370 ([M+H]+) 981 MS(ESI) m/z: ~ 980 N
F
365 ([M+H]+) 986 ~ I MS(ESI) m/z:
C/X-N 980 F 432 ([M+H]+) 982 MS(ESI) m/z:
365 ([M+H]+) Me 980 983 MS(ESI) m/z:
378 ([M+H]+) [Table 62]

CNJ

Me Ex Rl Syn (Sal) F 980 Dat 988 F MS(ESI) m/z:
980 F 447 ([M+H]+) 987 S MS(ESI) m/z: Cl 980 385 ([M+H]+) 989 MS(ESI) m/z:
413 ([M+H]+) ~ Me 980 980 990 MS(ESI) m/z: 996 MS(ESI) m/z:
393 ([M+H]+) CI 413 ([M+H]+) 991 ~N OMe MS(ESI) m/z: 997 FF MS(ESI) m/z:
360 ([M+H]+) 447 ([M+H]+) 992 F ~~ Me MS(ESI) m/z: 998 MS(ESI) m/z:
FF 451 ([M+H]+) 393([M+H]+) 980 _ 980 993 OMe MS(ESI) m/z: 999 ~~ CI MS(ESI) m/z:
409 ([M+H]+) 427([M+H] +) 994 \~ MS(ESI) mlz: 1000 iMe MS(ESI) m/z:
CI CI 447 ([M+H]+) 317([M+H] +) 995 \ d MS(ESI) m/z:
421 ([M+H]+) [Table 63]

N
H
Q

Ex Syn (Sal) Me 1029 Dat 1003 -N3-NMe MS(ESI) m/z:
Me 1029 0 435 ([M+H]+) 1001 -N ~ MS(ESI) m/z: 1029 Me 393 ([M+H]+) 1004 ~NOH MS(ESI) m/z:
SMe 1029 394 ([M+H]+) 1002 N~ \O MS(ESI) mlz:
428 ([M+H]+) Me 1029 - N 1029 1005 N N,,,Me MS(ESI) m/z: 1015 IN MS(ESI) m/z:
O 463 ([M+H]+) 433 ([M+H]+) -N~ 1029 1016 N MS(ESI) m/z:
1006 MS(ESI) m/z: 440 M+H +
OH ([ ] ) 394 ([M+H]+) I
N~ Me 1029 Me, N~ N 1029 1007 -N Me MS(ESI) m/z: 1017 ~'N YO MS(ESI) m/z:
407 ([M+H]+) 0 490 ([M+H]+) 0 -N N-~ 1029 - 1029 1008 NH2 MS(ESI) m/z: 1018 -N ~~ MS(ESI) m/z:
408 ([M+H]+) 440 ([M+H]+) N ~ 1029 1029 1009 N Me MS(ESI) m/z:
~ 1019 N~ N MS(ESI) m/z:
421 ([M+H]+) 447 ([M+H]+) 1010 - MS(ESI) m/z: _Na ~ N
1020 / MS(ESI) m/z:
392 ([M+H]+) 449 ([M+H]+) r' N 1029 1011 N MS(ESI) mlz: N 1029 419 ([M+H]+) 1021 ~N\ MS(ESI) m/z:
O N,Me 1029 Me 462 ([M+H]+) 1012 -N MS(ESI) m/z:

447 ([M+H]+) ON 1 ~ 1029 1022 N MS(ESI) m/z:
Me 1013 N MS(ESI) m/z: 462 ([M+H]+) 426 ([M+H]+) N 1029 N 1029 1023 MS(ESI) m/z:
1014 CN' MS(ESI) m/z: 454 ([M+H]+) Me 461 ([M+H]+) N 1029 1024 I MS(ESI) m/z:
OH 470 ([M+H]+) 1029 o 1029 0-0 1025 MS(ESI) m/z: 1035 N 5 MS(ESI) m/z:
456 ([M+H]+) 490 ([M+H]+) 1029 N r`p 1029 1026 CN,,rrO MS(ESI) m/z: 1036 \~N NJ MS(ESI) m/z:
O 461 ([M+H]+) 492 ([M+H]+) (-N 1029 ~Me 1029 1027 Me-N~,NJ MS(ESI) m/z: 1037 -N~N MS(ESI) m/z:
476 ([M+H]+) Me 379 ([M+H]+) N' 1029 1029 lJ'N~" 1028 MS(ESI) m/z: 1038 -N~N~ MS(ESI) m/z:
0 476 ([M+H]+) 419 ([M+H]+) p'- (""Ne 1029 1029 1029 ~Ny N./ MS(ESI) m/z: 1039 MS(ESI) m/z:
0 478 ([M+H]+) M 434 ([M+H]+) 1029 UN MS(ESI) m/z: -N 1029 1030 1040 ~ MS(ESI) m/z:
469 ([M+H]+) 350 ([M+H]+) 1029 ~ 1029 1031 N MS(ESI) m/z: 1041 N
MS(ESI) m/z:
461 ([M+H]+) HO
380 ([M+H]+) 1029 1032 J MS(ESI) m/z: N

~ 1042 /-Me MS(ESI) m/z:
476 ([M+H]+) N
H 407 ([M+H]+) ~ Me 1029 1033 C ~ N MS(ESI) m/z: -N N
478 ([M+H]+) 1043 a ` Me MS(ESI) m/z:
1029 407 ([M+H]+) N
1034 c MS(ESI) m/z: _N N~Me 1029 N\--4 p 476 ([M+H]+) 1044 MS(ESI) mlz:
393 ([M+H]+) [Table 64]

oo H L S R

Ex Rl Syn (Sal) N_N 1048 Dat 1049 F 0 Me MS(ESI) m/z:
HMe 1048 F 480 ([M+H]+) 1045 O MS(ESI) m/z: 1048 389 ([M+H]+) 1050 _--Me MS(ESI) m/z:
)aCF3 1048 346([M+H]
1046 MS(ESI) m/z: 1048 476 ([M+H]+) 1051 MS(ESI) m/z:
1048 422([M+H] +) 1047 Me MS(ESI) m/z: 1048 422 ([M+H]+) 1052 CI MS(ESI) m/z:
1048 456([M+H] +) 1048 S MS(ESI) m/z:
414 ([M+H]+) [Table 65]

O
N _ N t` ~ /
H
S
N
R

Ex R5 Syn (Sal) Me 1065 Dat 1054 Me MS(ESI) m/z:
1065 406 ([M+H]+) 1053 ,,/Me MS(ESI) m/z:
392 ([M+H]+) Me 1065 ~~CN 1065 1055 ~Me MS(ESI) m/z: 1066 MS(ESI) m/z:
434 ([M+H]+) 431 ([M+H]+) 1065 ~ 1065 1056 MS(ESI) m/z: 1067 CN MS(ESI) m/z:
404 ([M+H]+) 459 ([M+H]+) OEt 1065 ~~OH 1065 1057 MS(ESI) m/z: 1068 MS(ESI) m/z:
0 450 ([M+H]+) 422 ([M+H]+) 1058 OMe MS(ESI) m/z: 1069 MS(ESI) m/z:
450 ([M+H]+) 436 ([M+H]+) ~ 1065 1065 1059 OEt MS(ESI) m/z: 1070 OH MS(ESI) m/z:
464 ([M+H]+) OH 438 ([M+H]+) OEt 1065 1065 1060 MS(ESI) m/z: 1071 ~Me MS(ESI) m/z:
O 478 ([M+H]+) OH 436 ([M+H]+) 1061 OMe MS(ESI) m/z: 1072 MS(ESI) m/z:
O 462 ([M+H]+) 454 ([M+H]+) 1062 ~ OEt MS(ESI) m/z: 1073 MS(ESI) m/z:
O 476 ([M+H]+) 468 ([M+H]+) ~ 1065 ~O 1065 1063 OMe MS(ESI) m/z: 1074 \/ MS(ESI) m/z:
478 ([M+H]+) 484 ([M+H]+) ~ I MS(ESI) m/z:
1064 ~OEt MS(ESI) m/z: 1075 O
492 ([M+H]+) 498 ([M+H]+) 1065 ~ MS(ESI) m/z: 1076 MS(ESI) m/z:
417 ([M+H]+) 0 512 ([M+H]+) 1077 MS(ESI) m/z: 1085 MS(ESI) m/z:
N , Me 455 ([M+H]+) 475 ([M+H]+) 1078 MS(ESI) m/z: 1086 N MS(ESI) m/z:
455 ([M+H]+) 461 ([M+H]+) 1065 i/~ ~ 1065 1079 N MS(ESI) m/z: 1087 ~ N J MS(ESI) m/z:
455 ([M+H]+) 477 ([M+H]+) Me 1065 1065 1080 MS(ESI) m/z: 1088 N MS(ESI) m/z:
458 ([M+H]+) 475 ([M+H]+) \ N 1065 No 1065 1081 `- kS MS(ESI) m/z: 1089 MS(ESI) m/z:
461 ([M+H]+) 489 ([M+H]+) Me 1065 , Me 1065 1082 LNMe MS(ESI) m/z: 1090 N" Me MS(ESI) m/z:
435 ([M+H]+) 0 449 ([M+H]+) ~ Et 1065 , Et 1065 1083 ~N MS(ESI) m/z: 1091 lyNEt MS(ESI) m/z:
Et 463 ([M+H]+) 0 477 ([M+H]+) ~ Me 1065 1084 MS(ESI) m/z:
Me 449 ([M+H]+) [Table 66]

O
N N
N H ' ~_R
~
HO OH

Syn (Sal) N 980 Ex Rl Dat 1100 N MS(ESI) m/z:
980 384 ([M+H]+) 1092 MS(ESI) m/z: - 980 N
383 ([M+H]+) 1101 ~ 0 MS(ESI) m/z:
980 372 ([M+H]+) 1093 MS(ESI) m/z: 980 ci 416 ([M+H]+) 1102 -ND MS(ESI) m/z:
- 980 375 ([M+H]+) 1094 CI MS(ESI) m/z: 980 416 ([M+H]+) 1103 MS(ESI) m/z:
- 980 396([M+H] +) 1095 \ ~ MS(ESI) m/z: 980 CI CI 450 ([M+H]+) 1104 ~/ CI MS(ESI) m/z:
980 430([M+H] +) 1096 MS(ESI) m/z: 980 CF3 450 ([M+H]+) 1105 -00 MS(ESI) m/z:
980 376([M+H] +) 1097 \ ~ Me MS(ESI) m/z: 980 396 ([M+H]+) 1106 M MS(ESI) m/z:
O 980 334([M+H] +) 1098 N,Me MS(ESI) m/z: Me 980 412 ([M+H]+) 1107 Me MS(ESI) m/z:
980 348([M+H] +) 1099 S MS(ESI) m/z: Me 980 388 ([M+H]+) 1108 MS(ESI) m/z:
362([M+H] +) Me 980 980 1109 MS(ESI) m/z: 1111 MS(ESI) m/z:
Me 376([M+H] +) 374([M+HI
Me 980 980 1110 MS(ESI) m/z: 1112 MS(ESI) m/z:
404([M+H] +) 390([M+H] +) [Table 67]

N S \ CF3 H N/ ~ , Q
Ex Syn (Sal) OH 980 Dat 1115 OH MS(ESI) m/z:
n 980 464([M+H]+) 1113 U -Me MS(ESI) m/z:
461([M+H]+) 1114 OH MS(ESI) m/z:
490([M+H] +) [Table 68]

N N\ N_R1 u ~

CNJ

Ex Rlu Syn (Sal) 0 1116 Dat 1124 OH MS(ESI) m/z:
0 1116 487([M+H] +) 1116 Me MS(ESI) m/z: 0 1116 485([M+H]+) 1125 OH MS(ESI) m/z:
O 1116 501([M+H] +) 1117 ~Me MS(ESI) m/z: 0 Me 1116 499([M+H] +) 1126 ZK_"XN MS(ESI) m/z:
O 1116 Me 514([M+H] +) 1118 Me MS(ESI) m/z: 0 Me 1116 513([M+H] +) 1127 Me MS(ESI) m/z:
0 1116 528([M+H] +) 1119 Me MS(ESI) m/z: 0 1116 527([M+H] +) 1128 MS(ESI) m/z:
O Me 1116 511([M+H] +) 1120 MS(ESI) m/z: 0 1116 Me 499([M+H] +) 1129 /1-0 MS(ESI) m/z:
O Me 1116 525([M+H] +) 1121 "X{Me MS(ESI) m/z: 0 1116 527([M+H] +) 1130 MS(ESI) m/z:
O 1116 539([M+H] +) 1122 ~O~ Me MS(ESI) m/z: H 1116 501([M+H] *) 1131 >-~D MS(ESI) m/z:
0 Me 1116 522([M+H] +) 1123 '" O"' MS(ESI) mlz: 0 NMe 1116 515([M+H] +) 1132 MS(ESI) m/z:
536([M+H] +) 1133 MS(ESI) m/z: 1144 MS(ESI) m/z:
534([M+H] +) F 551([M+H] +) 1134 MS(ESI) m/z: 1145 MS(ESI) m/z:
N 534([M+H] +) 551([M+H]+) 1135 N MS(ESI) m/z: 1146 F MS(ESI) m/z:
534([M+H] +) 551([M+H] +) 1136 N MS(ESI) m/z: 1147 MS(ESI) m/z:
535([M+H] +) O- M e 563([M+H] +) 1137 r~ ,~ MS(ESI) m/z: 1148 MS ESI m/z:
N Me ( ) 535([M+H] +) 563([M+HI +) 1138 MS(ESI) m/z: 1149 Me MS(ESI) m/z:
539([M+H] +) O 563([M+H] +) 1139 MS(ESI) m/z: 1150 MS(ESI) m/z:
539([M+H] +) F 565([M+H] +) 1140 MS(ESI) m/z: 1151 MS(ESI) m/z:
533([M+H] +) F
565([M+H] +) 1141 ,/ MS(ESI) m/z: 1152 MS(ESI) m/z:
Me 547([M+H] +) 565([M+H] +) O Me 1116 0 1116 1142 MS(ESI) m/z: 1153 MS(ESI) m/z:
547([M+H] +) 559([M+H] +) 1143 1/ Me MS(ESI) m/z: 1154 MS(ESI) m/z:
547([M+H] +) 562([M+H] +) 0 1116 Me 1162 1155 MS(ESI) m/z: 1165 MS(ESI) m/z:
561 ([M+H] +) 485([M+H] +) Me 1162 1156 ~ 1116 MS(ESI) m/z: 1166 MS(ESI) m/z:
575([M+H] +) 487([M+H] +) Me 1162 1116 1167 MS(ESI) m/z:
1157 MS(ESI) m/z: 499([M+H] +) 573([M+H] +) 1162 1168 MS(ESI) m/z:
1116 513([M+H] +) 1158 MS(ESI) m/z: ~ 1162 ~ 589([M+H] +) 1169 N MS(ESI) m/z:
0 1116 520([M+H] +) 1159 MS(ESI) m/z: Me 1162 609([M+H] +) 1170 MS(ESI) m/z:
1116 533([M+H] +) 1160 MS(ESI) m/z: 1162 609([M+H]+) 1171 Me MS(ESI) m/z:
533([M+HI +) 1161 MS(ESI) m/z: 1172 MS(ESI) m/z:
0 609([M+H] +) 547([M+H] +) 1173 Me MS(ESI) m/z: 173 MS(ESI) m/z:
0-Me 549([M+HI +) 471 ([M+H] +) 1163 MS(ESI) m/z: 1174 Me MS(ESI) m/z:
0 549([M+H] +) 483([M+H] +) Me 1162 1164 1175 Me MS(ESI) m/z:
Me MS(ESI) m/z: 485([M+H] +) 549([M+HI +) 1162 -~ S 1178 1176 MS(ESI) m/z: 1186 I I MS(ESI) m/z:
CO2H 563([M+H] +) 0 575([M+H] +) 1162 1178 --o 1177 MS(ESI) m/z: 1187 -S MS(ESI) m/z:

CO2H 563([M+H] +) 0 575([M+H] +) ~ 1178 0 1178 1188 MS(ESI) m/z:
1178 -S-Me MS(ESI) m/z: 0 O 507([M+H] +) 583([M+H] +) MS(ESI) m/z:
1179 -S~"\Me MS(ESI) m/z: p 587 M+H
([ ] +) 0 521(LM+H] +) 0 _~ 1178 1180 -S MS(ESI) m/z: O MS(ESI) m/z:
587([M+H] +) O 533([M+H] +) 0 Me 1178 - 11 11 1181 S~ MS(ESI) m/z: 1191 O \~ MS(ESI) m/z:
0 Me 535([M+H] +) F 587(LM+H] +) //,\\o ~~ Me 1178 - IS OI
1182 MS(ESI) m/z: 1192 i~ MS(ESI) m/z:
~ 589(LM+H] +) ~ 535([M+H] +) ~ ` ^ 1178 1178 1183 -S/^v `Me MS(ESI) m/z: 1193 -S MS(ESI) m/z:

11 0 597([M+H] +) O 549([M+H] +) 11 1178 cp 1184 MS(ESI) m/z: 1194 MS(ESI) m/z:.
O 569([M+H] +) -S 645([M+H] +) O
1185 S 0\/ MS(ESI) m/z: _S 1178 O 575([M+H] +) 1195 MS(ESI) m/z:
645([M+H] +) O Me 1196 S Me 1196 1196 ~N Me MS(ESI) m/z: 1200 /\N--~ MS(ESI) m/z:
H 514([M+H] +) H Me 530([M+HI +) 0 1196 s ~ 1196 /
1197 H MS(ESI) m/z: 1201 H -- MS(ESI) m/z:
548([M+Hl +) 564([M+H] +) 0 1196 s _-1196 1198 H MS(ESI) m/z: 1202 N \/ MS(ESI) m/z:
562([M+H] +) 578([M+H] +) 1199 -.Me 'AN H MS(ESI) m/z:
502([M+H] +) NMR data of several Example compounds are shown in the following Table 69. For the data, tetramethylsilane was used as an internal standard, and unless otherwise specifically mentioned, 8(ppm) of the peaks in 'H-NMR using DMSO-d6 as a measurement solvent is shown.

(CDC13) : S(ppm) of the peaks in 'H-NMR in CDC13.
[Table 69]

Ex Dat(NMR) 2.65-2.83(4H,m),2.91-2.97(4H,m),2.97(2H,s),3.63 (3H,s),3.68(2H,s),7.09(1 H,dd,J
11 =8.0,2.OHz),7.18(1H,brs),7.13(1H,d,J=2.OHz),7.25(1H,brs),7.59-7.64(3H,m),8.1 2-8.17(2H,m),8.40(1H,d,J=7.5Hz),852(1 H,s).

(CDC13) 32 3.18(2H,t,J=5.4Hz),3.59-3.65(2H,m),3.78(2H,s),6.39(1H,brs),7.13-7.23(2H,m),7.
25-7.30(1 H,m),7.43 -7.53 (3H,m),7.92-7.97(2H,m),8.20(l H,s),8.59(1 H,dd,J=8.3,1 .4Hz),10.50(1 H,brs) 1.91 (2H, d, J = 10.8 Hz), 1.99-2.08 (2H, m), 2.33-2.39 (1H, m), 2.75 (2H, t, J
10.8 Hz), 3.04 (2H, d, J = 11.6 Hz), 3.17-3.22 (2H, m), 3.39-3.44 (2H, m), 4.66 40 (1H, t, J = 5.4 Hz), 7.11-7.21 (2H,m),7.34(1H,d,J=8Hz),7.55-7.58(1H,m), 7.64-7.68 (2H, m), 7.84 (1H, t, J = 5.4 Hz), 8.13 (2H, d, J = 7.6 Hz), 8.50-8.52 (2H, m), 10.48 (1 H, s) 2.16 (2H, q, J = 6.8 Hz), 3.04-3.21 (3H, m), 3.27-3.40 (2H, m), 6.93 (1H, brs), 69 7.05-7.14 (2H, m), 7.22 (1H, d, J = 6.8 Hz), 7.43 (1H, brs), 7.54-7.61 (3H, m), 8.08-8.10 (2H, m), 8.15-8.17 (1H, d, J = 9.6 Hz), 8.50 (1H, s), 10.19 (1H, s) 1.73 -1.90(4H,m),2.3 8-2.49(1 H,m),3.09-3.18 (2H,m),3.92-4.03 (2H,m),6.85 (1 H,brs 105 ),7.30(1H,brs),7.40(1H,d,J=7.OHz),7.53-7.62(4H,m),8.10-8.14(2H,m),8.34(1H,d, J=7.OHz),8.58(1 H,s),8.78(1 H,brs),10.18(1 H,brs).
3.27 (4H, brs), 3.40-3.60 (2H, m), 3.67-3.70 (2H, m), 4.06 (2H, s), 7.19-7.28 (2H, 109 m), 7.3 5(1 H, d, J = 7.7 Hz), 7.77 (1 H, brs), 8.20 (1 H, brs), 8.27 (2H, d, J= 6.2 Hz), 8.45 (1 H, dd, J = 1.5, 8.0 Hz), 8.81 (1 H, s), 9.02 (2H, d, J = 6.0 Hz) 3.19-3.63 (12H, m), 3.80-3.83 (4H, m), 3.97 (2H, brs), 7.13-7.23 (2H, m), 7.31 151 (1H, dd, J = 7.7,1.0 Hz), 7.71 (1H, s), 7.72 (1H, brs), 8.13 (1H, brs), 8.43 (1H, dd, J = 8.1,1.5 Hz), 9.73 (1H, brs), 10.78 (1H, brs) 1.85-2.00 (2H, m), 2.27 (2H, d, J = 11.3 Hz), 2.76 (2H, t, J= 11.3 Hz), 3.06-3.24 215 (4H, m), 3.28-3.45 (3H, m), 3.45-3.55 (4H, m), 3.72-3.84 (4H, m), 3.92-4.08 (4H, m), 7.07-7.22 (2H, m), 7.30 (1H, dd, J = 7.7,1.6 Hz), 7.71 (1H, s), 8.42 (1H, dd, J= 7.9,1.6 Hz), 9.64 (1 H, s), 11.66 (1 H, brs) 1.76-1.96(4H,m),2.26-2.3 8 (1 H,m),2. 80-2.92(2H,m),3.10-3 .18(2H,m),3 .47-3 .53 (4 229 H,m),3.73-3.81(4H,m),6.88(1H,brs),7.40(1H,brs),7.95(1H,s),8.62(1H,d,J=6.5Hz) ,8.74(1H,s),8.80(1H,d,J=6.5Hz),10.57(1H,s).
234 1.51 (2H, d, J = 13.0 Hz), 1.85-1.93 (2H, m), 3.07-3.24 (6H, m), 3.46-3.49 (4H, m), 3.73-3.76 (4H, m), 5.36 (2H, br), 7.22 (1 H, dd, J= 8.0,5.2 Hz), 7.73 (1 H, s), 8.08 (1H, dd, J= 5.1,1.6 Hz), 8.68 (1H, dd, J = 8.0,1.5 Hz), 9.67 (1H, s) 1.54-1.63 (2H, m), 1.90-1.95 (2H, m), 3.11-3.19 (4H, m), 3.36-3.42 (2H, m), 311 3.63-3.69 (4H, m), 3.78-3.85 (3H, m), 3.97 (2H, s), 4.74 (1H, brs), 6.99 (1H, dd, J= 11.6, 8.5 Hz), 7.31 (1 H, ddd, J= 6.2, 8.3, 8.5 Hz), 7.65 (1 H, s), 7.78 (1 H, s), 8.31 (1H, d, J = 8.3 Hz), 8.39 (1H, s), 10.18 (1H, s), 10.67 (1H, brs) 3.18-3.30 (9H, m), 3.57 (3H, s), 3.63-3.74 (6H, m), 4.01 (2H, brs), 7.12-7.24 (2H, 356 m), 7.32 (1 H, d, J = 7.8 Hz), 8.17 (1 H, brs), 8.44 (1 H, dd, J = 8.0,1.4 Hz), 10.67 (1H, brs) 1.85-2.17 (4H, m), 2.88-3.00 (1H, s), 3.08-3.24 (5H, m), 3.29 (3H, s), 3.50-3.66 379 (4H, m), 3.70 (2H, t, J = 5.3 Hz), 3.89 (2H, d, J= 4.0 Hz), 7.13 (1H, td, J = 8.4, 2.7 Hz), 7.31 (1H, dd, J = 8.7, 6.5 Hz), 7.49-7.59 (2H, m), 7.69 (1H, s), 8.06 (1H, s), 9.65 (1H, s), 9.99 (1H, brs) 1.79-1.90 (4H, m), 2.25-2.34 (1H, m), 2.77-2.86 (2H, m), 3.14 (3H, s), 3.22-3.26 (2H, m), 3.27 (3H, s), 3.61-3.73 (4H, m), 6.77 (1H, brs), 7.20 (1H, dd, J =
8.0,5.0 380 Hz), 7.31 (1H, brs), 7.57 (1H, s), 8.08 (1H, dd, J= 4.9,1.8 Hz), 8.68 (1H, dd, J
8.0,1.5 Hz), 9.73 (1 H, s) 3.16(3 H,s),3.30(3H,s),3.32-3.52(6H,m),3.61-3.67(4H,m),3.69-3.74(2H,m),4.00(2 H,s),7.23(1H,dd,J=8.0,5.OHz),7.60(1H,s),7.74(1H,brs),8.12(1H,dd,J=5.0,1.5Hz), 8.14(1 H,brs),8.64(1 H,dd,J=8.0,1.5Hz),9.47(1 H,s),10.69(1 H,brs).
1.80-1.88 (2H, m), 1.99-2.02 (2H, m), 2.74-2.80 (2H, m), 2.99-3.02 (2H, m), 3.76 449 (1 H, brs), 4.85 (1 H, d, J = 3.2 Hz), 7.09-7.19 (2H, m), 7.29 (IH, dd, J=
7.2,1.6 Hz), 7.57-7.65 (3H, m), 8.10-8.13 (2H, m), 8.39 (1H, dd, J = 8.0,1.6 Hz), 8.93 (1 H, s), 10.24 (1 H, s) 3.21-3.23 (2H,m),3.50-3.78(6H,m),4.90(2H,brs),7.05(1 H,t,J=8.2Hz),7.30-7.3 8(1 462 H,m),7.75(1H,s),8.26-8.32(2H,m),8.44-8.45(1H,m),9.25(1H,s),9.68(1H,d,J=5.3H
z),9.83(1H,s),10.06(1H,s) 1.87-1.90(2H,m),2.02-2.12(2H,m),2.31-2.41(1 H,m),2.77(1 H,t,J=10.8Hz),2.99-3.
468 03(2H,m),6.59(1H,d,J=9.6Hz),6.93(1H,brs),7.09-7.20(2H,m),7.29-7.31(1H,d,J=7 .3Hz),7.41(1 H,brs),8.14(1 H,d,J=2.6Hz), 8.19-8.23 (1 H,m),8.37(1 H,d,J=7.4Hz), 8.8 0(1 H,s),10.24(1 H,brs).
1.86-1.91(2H,m),2.05-2.15(2H,m),2.40-2.51(1 H,m),2.78(2H,t,J=10.7Hz),2.98-3.
476 02(2H,m),7.10-7.22(2H,m),7.30-7.33(2H,m),7.43-7.45(1H,m),7.84(2H,brs),8.14( 1 H,d,J=6.7Hz), 8.40-8.43 (1 H,m),8.65(1 H,brs),9.16(1 H,s),10.27(1 H,brs).

1.87-1.91(2H,m),2.03-2.15 (2H,m),2.43-2.51(1 H,m),2.88 (2H,t,J=11.4Hz),3.29-3.
477 33(2H,m),7.21-7.27(2H,m),7.41-7.43(1H,m),7.81-7.83(2H,m),8.08-8.16(2H,m),8 .63-8.66(1 H,d,m),8.77(1 H,brs),9.21(1 H,d,J=1.3Hz),9.79(1 H,brs).
3.22 (4H, brs), 3.37 (4H, brs), 3.49-3.51 (4H, m), 3.75-3.77 (4H, m), 4.00 (2H, s), 482 7.05 (1 H, ddd, J = 2.9, 8.9, 11. 5 Hz), 7.18 (1 H, dd, J = 2.9, 10.1 Hz), 7.69 (1 H, s), 8.10 (1H, s), 8.33 (1H, s), 8.36 (1H, dd, J = 6.0, 8.9 Hz), 9.28 (1H, s), 10.77 (1H, brs) 1.81-1.84 (2H, m), 1.89-1.99 (2H, m), 2.27 (1H, dddd, J = 4.1, 4.1, 11.8, 11.8 Hz), 2.67-2.74 (2H, m), 2.93-2.96 (2H, m), 3.48-3.50 (4H, m), 3.71-3.73 (4H, m), 492 6.80 (1H, s), 7.07 (1H, ddd, J = 1.5, 7.6, 8.9 Hz), 7.14 (1H, ddd, J =
1.4, 7.9, 8.9 Hz), 7.25 (1 H, dd, J= 1.4, 7.6 Hz), 7.29 (1 H, s), 8.27 (1H, s), 8.37 (1 H, dd, J
1.5, 7.9 Hz) 1.84-1.98 (4H, m), 2.33 (1H, dddd, J = 4.4, 4.4, 11.6, 11.6 Hz), 2.85-2.91 (2H, m), 3.30-3.33 (2H, m), 3.48-3.51 (4H, m), 3.70-3.73 (4H, m), 6.83 (1H, brs), 7.24 501 (1 H, dd, J = 5.2, 8.1 Hz), 7.34 (1 H, brs), 8.08 (1 H, dd, J = 1.6, 5.2 Hz), 8.36 (1H, s), 8.66 (1H, dd, J = 1.6, 8.2 Hz), 9.55 (1H, s) 1.87-1.92 (4H, m), 2.22-2.35 (1H, m), 2.73-2.78 (2H, m), 3.09 (3H, s), 3.19-3.22 599 (2H, m), 3.26 (3H, s), 3.57-3.61 (4H, m), 6.76 (1H, s), 7.14 (1H, dd, J =
4.8, 7.6 Hz), 7.28 (1H, s), 8.05-8.06 (1H, m), 8.23 (1H, s), 8.60-8.62 (1H, m), 9.47 (1H, s) 2.82(3 H,d,J=4.4Hz),3.17-3.30(6H,m),3.54-3.66(2H,m),7.19(1 H,td,J=7.8,1.5Hz), 7=26(1H,td,J=7.8,1.5Hz),7.33(1H,dd,J=7.8,1.5Hz),7.82(1H,dd,J=7.8,5.4Hz),8.43( 1 H,dd,J=8.3,1.4Hz), 8.59-8.63 (1 H,m),8.67(1 H,s),8.85(1 H,dd,J=4.9,1.5Hz),9.40(1 H,d,J=2.OHz),10.25(1 H,s),11.45(1 H,brs) 1.84-1.92 (4H, m), 2.24-2.32 (1H, m), 2.66-2.73 (2H, m), 2.94-2.97 (2H, m), 671 3.42-3.45 (2H, m), 3.86-3.89 (2H, m), 3.92 (2H, brs), 6.81 (1H, brs), 7.08 (1H, dd, J = 7.5, 7.6 Hz), 7.15 (1 H, dd, J = 7.5, 8.1 Hz), 7.28 (1H, d, J = 7.6 Hz), 7.34 (1H, brs), 7.66 (1H, s), 8.31 (1H, s), 8.43 (1H, d, J = 8.1 Hz), 10.24 (1H, s) 1.82-1.95 (2H, m), 1.98-2.13 (2H, m), 2.58-3.14 (8H, m), 3.32 (2H, s), 3.57-3.73 701 (4H, m), 4.90-5.07 (1H, m), 7.09-7.19 (2H, m), 7.30 (1H, dd, J= 7.8,1.4 Hz), 7.64 (1 H, s), 8.43 (1 H, dd, J = 8.1,1.5 Hz), 10.12 (1 H, brs) 1.99-2.13 (4H, m), 3.18 (3H, brs), 3.40-3.44 (2H, m), 3.57-3.68 (8H, m), 716 4.01-4.06 (3H, m), 7.13-7.33 (3H, m), 7.57 (1H, m), 7.74 (1H, s), 8.14 (1H, s), 8.46 (1H, dd, J= 1.2, 7.6 Hz), 9.86 (1H, s), 10.61 (1H, brs) 2.79-2.81 (4H, m), 3.19-364 (8H, m), 3.86-3.89 (4H, m), 4.01 (1H, brs), 7.15 722 (1H, ddd, J = 1.5, 7.7, 7.8 Hz), 7.21 (1H, ddd, J = 1.4, 7.7, 7.9 Hz), 7.32 (1H, dd, J = 1.4, 7.8 Hz), 7.67 (1 H, s), 7.74 (1 H, brs), 8.14 (1 H, brs), 8.44 (1 H, dd, J = 1. 5, 7.9 Hz), 9.71 (1 H, s), 10.74 (1 H, brs) 3.23 (4H, brs), 3.45-3.65 (4H, m), 4.11 (2H, brs), 7.15-7.26 (3H, m), 7.32 (1H, 862 dd, J = 1.4, 7.8 Hz), 7.74 (1 H, brs), 7.96 (1 H, s), 8.09 (1 H, brs, J =
1.6, 7.8 Hz), 8.64 (1H, s), 8.90 (1H, s), 9.61 (1H, brs) Industrial Applicability The compound of the present invention has a potent trkA receptor inhibitory activity, and is useful as a medicine, particularly as an agent for treating urinary frequency, urinary urgency, urinary incontinence, lower urinary tract pain, which are associated with various lower urinary tract diseases including overactive bladder, and various diseases accompanied by pain.

Claims (15)

1. An azolecarboxamide derivative represented by following the general formula (I) or a salt thereof:

(wherein symbols have the following meanings:
X: S or O, A: phenylene which may be substituted, pyridinediyl which may be substituted, pyrimidinediyl which may be substituted, thiophenediyl which may be substituted, pyrazolediyl which may be substituted, pyridonediyl which may be substituted, Q: a monocyclic or bicyclic alicyclic nitrogen-containing heterocyclic group which may be substituted, R1: halogen, lower alkylcarbonyl, C1-C7 alkyl which may be substituted, lower cycloalkyl which may be substituted, lower alkoxy which may be substituted, aryl which may be substituted, heteroaryl which may be substituted, a group represented by the general formula (II), the general formula (III), or the general formula (IV);

R1a and R1b: each independently -H, lower alkyl which may be substituted, lower cycloalkyl, a saturated heterocyclic group which may be substituted, lower alkylcarbonyl, lower alkoxycarbonyl, aryl, or heteroaryl, R1c : -H or lower alkyl, Y1: lower alkylene which may be substituted in which -O-, -S-, -SO-, -SO2-, or -N(-R1d)- may be contained between carbons thereof, R1d: -H, lower alkyl, lower alkylcarbonyl, lower alkoxycarbonyl, or aryl-lower alkyl, Y2: lower alkylene in which -O-, -S-, -SO2-, -N(-R1e)-, -N(-CO-R1f)-, -N(-CO-NH-R1g)-, -N(-CS-NH-R1g)-, or -N(-SO2-R1h)- may be contained between carbons thereof, R1e: -H or lower alkyl which may be substituted, R1f: lower alkyl which may be substituted, lower cycloalkyl, lower alkoxy, aryl which may be substituted, heteroaryl which may be substituted, or aryl-lower alkenyl, R1g: -H, lower alkyl, aryl, or aryl-lower alkyl, R1h: lower alkyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl which may be substituted, heteroaryl, or aryl-lower alkyl, and R2: -H, halogen, or a nitrogen-containing saturated heterocyclic group).
2. The derivative according to claim 1, wherein A, Q
or R1 have the following meanings, or a salt thereof, A:

R3: -H, halogen, lower alkyl, cyano, cyano-lower alkyl, hydroxy-lower alkyl, lower alkoxy, halogeno-lower alkoxy, lower alkoxy-lower alkyl, lower alkenyl, cyano-lower alkenyl, carboxy, carbamoyl, lower alkoxycarbonyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl, lower alkylaminocarbonyl-lower alkyl, lower alkylsulfonyl, aminosulfonyl, or lower alkylsulfinyl, R4: -H, halogen, or lower alkoxy, R3 and R4 in combination may be bridged as -O-lower alkylene, R5: -H or halogen, R6: -H or lower alkyl, Q: a group represented by the general formula (V), (VI), (VII), (VIII) or (IX):

V1 and V2: each independently C1-3 alkylene, V3: methylene or ethylene, W: -CH(-R9)-, -N(-R9)-, -O-, -S-, -SO-, or -SO2-, R7 and R8: each independently -H, halogen, hydroxy, lower alkyl, hydroxy-lower alkyl, carboxy, lower alkoxycarbonyl, lower alkylcarbonyloxy, carbamoyl, aryl, aryl-lower alkyl, a saturated heterocyclic group which may be substituted with lower alkyl, or an -Alk-saturated heterocyclic group, -Alk-: lower alkylene, two substituents of R7, R8 and R9 in combination may be bridged as lower alkylene, R7 and R8 may be substituted with the same carbon atoms, or in combination may form an oxo group, or a nitrogen-containing saturated heterocyclic group having spiro bonds, wherein the nitrogen-containing saturated heterocyclic group may be substituted with lower alkyl or an oxo group, R9: -H, lower alkyl, cyano, hydroxy, lower alkoxy, lower alkenyl, lower alkoxycarbonyl-lower alkenyl, lower alkylsulfonyl, -Alk-R9a, -CO-R9b, -Alk-CO-R9b, -CO-Alk-R9c , -NR9d R9e, aryl, aryloxy, or a saturated heterocyclic group, wherein the nitrogen-containing saturated heterocyclic group may be substituted with lower alkyl, hydroxy, or an oxo group, -Alk-: lower alkylene, R9a: cyano, hydroxy, lower alkoxy, mono- or dihydroxy-lower alkyl, aryl, aryloxy, arylcarbonyloxy, amino which may be substituted with lower alkyl, lower alkoxycarbonylamino, heteroaryl, or a saturated heterocyclic group, wherein the heteroaryl may be substituted with lower alkyl or an oxo group, and the saturated heterocyclic group may be substituted with a lower alkyl group, R9b: lower alkyl, hydroxy, lower alkoxy, -NR9f R9g or an alicylic heterocyclic group, wherein the alicyclic heterocyclic group may be substituted with lower alkyl, hydroxy, carboxy, lower alkoxycarbonyl, mono- or di-lower alkylamino, a saturated heterocyclic group, or an -Alk-saturated heterocyclic group, -Alk-: lower alkylene, R9f and R9g: each independently -H, lower alkyl, hydroxy-lower alkyl, lower cycloalkyl which may be substituted with amino, lower alkoxy-lower alkyl, mono- or di-lower alkylamino-lower alkyl, lower alkylsulfonyl, heteroaryl, or a saturated heterocyclic group, wherein the saturated heterocyclic group may be substituted with lower alkyl or aryl-lower alkyl, or an -Alk-saturated heterocyclic group, -Alk-: lower alkylene, R9c: lower alkoxy, lower alkylcarbonyloxy, or a saturated heterocyclic group, wherein the saturated heterocyclic group may be substituted with lower alkyl or an oxo group, R9d and R9e: each independently -H, lower alkyl, lower alkylcarbonyl, or carbamoyl-lower alkyl, R1: halogen, lower alkylcarbonyl, lower cycloalkyl which may be substituted with hydroxy, lower alkoxy which may be substituted with lower alkoxy, C1-C7 alkyl which may have a substituent selected from the following G1 group, aryl, heteroaryl, a group represented by the general formula (X), (XI), (XII), (XIII), or (XIV), wherein the aryl or heteroaryl may have one or two substituent(s) selected from the following G2 group, and the two substituents in combination may form a cyclic structure, G1 group: hydroxy, lower alkoxy, N-lower alkyl-N-lower alkoxy-lower alkylamino, mono- or di-lower alkylamino, a saturated heterocyclic group, aryl or aryloxy, wherein the aryl or aryloxy may be substituted with halogen, and halogeno-lower alkyl, G2 group: halogen, hydroxy, oxo, lower alkyl, halogeno-lower alkyl, lower alkoxy, cyano, carboxy, carbamoyl, and -NR1i R1j, R1i and R1j: each independently -H, lower alkyl, lower alkoxy-lower alkyl, or lower alkoxycarbonyl, R1p and R1q: each independently -H, lower cycloalkyl, lower alkylcarbonyl, lower alkoxycarbonyl, aryl, heteroaryl, a saturated heterocyclic group, or lower alkyl which may have a substituent selected from the following G3 group, wherein the saturated heterocyclic group may have a substituent selected from the group consisting of lower alkyl which may substituted with one or two aryl(s), and aryl-lower alkoxycarbonyl, G3 group: halogen, hydroxy, cyano, lower alkoxy, lower alkoxy-lower alkoxy, aryl, heteroaryl, a saturated heterocyclic group, carboxy, lower alkoxycarbonyl, lower alkylsulfanyl, lower alkylsulfinyl, lower alkylsulfonyl, carbamoyl which may be substituted with lower alkyl, and -NR1k R1l, R1k and R1l: each independently -H, lower alkyl, lower alkylcarbonyl, lower alkoxycarbonyl, or lower alkylsulfonyl, k: 0, 1 or 2, Y3: a single bond, -CH2-, -O-, -N(-R1m)-, -S-, -SO-, or -SO2-, R1m: -H, lower alkyl, lower alkylcarbonyl, lower alkoxycarbonyl, or aryl-lower alkyl, R1r and R1s: each independently -H, halogen, hydroxy, lower alkyl, lower alkoxy, hydroxy-lower alkyl, lower alkoxy-lower alkyl, lower alkylcarbonyloxy, carboxy, lower alkoxycarbonyl, carbamoyl, mono- or di-lower alkylamino-lower alkyl, aryl or -CO-NH-Alk-R1n, -Alk-: lower alkylene, R1n: hydroxy or a saturated heterocyclic group, wherein R1r and R1s in combination may be bridged as lower alkylene, and R1r and R1s may be substituted with the same carbon atom, and may form an oxo group, m: 0, 1, or 2, n: 1, 2, 3, or 4, R1t: -H or lower alkyl, R1u: -H, lower alkyl, -Alk-R1w, -CO-R1x, -SO2-R1y, or -CS-NH-R1z, -Alk-: lower alkylene, R1W: lower cycloalkyl, lower alkoxy, carboxy, carbamoyl, a saturated heterocyclic group, or aryl, heteroaryl, wherein the aryl may have a substituent selected from the group consisting of lower alkyl, lower alkoxy and a carboxy group, R1x: lower alkyl, lower cycloalkyl, hydroxy-lower alkyl, lower alkoxy, lower alkoxy-lower alkyl, amino, lower alkylamino, arylamino, aryl-lower alkylamino, mono- or di-lower alkylamino-lower alkyl, aryl, aryl-lower alkyl which may be substituted with halogen, aryl-lower alkenyl, heteroaryl, or heteroaryl-lower alkyl, wherein the aryl or heteroaryl may have a substituent selected from the group consisting of halogen, lower alkyl, lower alkoxy, and aryl, R1y: lower alkyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl, aryl-lower alkyl, or heteroaryl, wherein the aryl may have a substituent selected from the group consisting of halogen and aryl, R1z: lower alkyl, aryl, aryl-lower alkyl, R1v: -H or lower alkoxycarbonyl, Y4: -O-, -S-, or -SO2-, and h: 0 or 1.
3. The derivative according to claim 1 or 2, wherein A has the following meaning,or a salt thereof, A:

R13: -H, halogen, lower alkyl, cyano, cyano-lower alkyl, hydroxy-lower alkyl, lower alkoxy, halogeno-lower alkoxy, lower alkoxy-lower alkyl, lower alkenyl, cyano-lower alkenyl, carboxy, carbamoyl, lower alkoxycarbonyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, carbamoyl-lower alkyl, mono- or di-lower alkylaminocarbonyl-lower alkyl, lower alkylsulfonyl, aminosulfonyl or lower alkylsulfinyl, R14: -H, halogen or lower alkoxy.
4. The derivative according to any one of claims 1 to 3, wherein Q has the following meaning, or a salt thereof, Q:

R17 and R18: each independently -H, halogen, hydroxy, lower alkyl, hydroxy-lower alkyl, carboxy, lower alkoxycarbonyl, lower alkylcarbonyloxy, carbamoyl, aryl or aryl-lower alkyl, R19: -H, lower alkyl, cyano, hydroxy, lower alkoxy, lower alkenyl, lower alkoxycarbonyl-lower alkenyl, lower alkylsulfonyl, -Alk-R9a, -CO-R19b, -Alk-CO-R19b, -CO-Alk-R9c, -NR9d R9e, aryl, aryloxy, or a saturated heterocyclic group, wherein the saturated heterocyclic group may be substituted with lower alkyl, hydroxy or an oxo group, -Alk-: lower alkylene, R9a, R9c, R9d, and R9e have the same meanings as described above, R19b: lower alkyl, hydroxy, lower alkoxy, -NR19f R19g or an alicylic heterocyclic group, wherein the alicyclic heterocyclic group may be substituted with lower alkyl, hydroxy, carboxy, lower alkoxycarbonyl, or mono- or di-lower alkylamino, R19f and R19g: each independently -H, lower alkyl, hydroxy-lower alkyl, lower cycloalkyl which may be substituted with amino, lower alkoxy-lower alkyl, mono- or di-lower alkylamino-lower alkyl, lower alkylsulfonyl, heteroaryl, or a saturated heterocyclic group which may be substituted with lower alkyl.
5. The derivative according to any one of claims 1 to 4, wherein R1 has the following meaning, or a salt thereof, R1:

-Alk-: lower alkylene, R11a: -H or lower alkyl, R11b: -H, lower alkyl, lower cycloalkyl, hydroxy-lower alkyl, or lower alkoxy-lower alkyl, R11c: -H, hydroxy, lower alkyl, hydroxy-lower alkyl, or lower alkoxy-lower alkyl, R11d: -H, hydroxy, lower alkoxy, a saturated heterocyclic group, or aryl, wherein the aryl may have a substituent selected from the group consisting of halogen and halogeno-lower alkyl, R11e: -H, lower alkyl, -Alk-R1w, -CO-R11x, or -SO2-R11y -Alk-: lower alkylene, R1w has the same meaning as described above, R11x: lower alkyl, lower cycloalkyl, hydroxy-lower alkyl, lower alkoxy, lower alkoxy-lower alkyl, amino, lower alkylamino, arylamino, aryl-lower alkylamino, di-lower alkylamino-lower alkyl, aryl, aryl-lower alkyl, aryl-lower alkenyl, heteroaryl, or heteroaryl-lower alkyl, wherein the aryl may have a substituent selected from the group consisting of halogen, lower alkyl, and lower alkoxy, R11y: lower alkyl, lower cycloalkyl, lower cycloalkyl-lower alkyl, aryl which may be substituted with halogen, aryl-lower alkyl, or heteroaryl, R11f: -H or hydroxy, R11g: -H, halogen, hydroxy, oxo, lower alkyl, halogeno-lower alkyl, lower alkoxy, cyano, carboxy, carbamoyl, or -NR11i R11j, R11i and R11i: each independently -H, lower alkyl, lower alkoxy-lower alkyl, or lower alkoxycarbonyl, R11h: -H or lower alkyl.
6. The derivative according to Claim 5, wherein A, Q, R1 and R2 have the following meanings, or a salt thereof, A:

Q:

R2: -H, R13 and R14: the same as in claim 3, R17, R18, and R19: the same as in claim 4, R11a, R11b, R11c, and R11g: the same as in claim 5.
7. The derivative according to Claim 6, wherein R13 is -H, halogen or lower alkoxycarbonyl-lower alkyl; R14, R17 and R18 are each -H; R19 is -H, hydroxy, carbamoyl or aminocarbonyl-lower alkyl; R11a is lower alkyl; R11b is lower alkoxy-lower alkyl; and R11c and R11g are each -H, or a salt thereof.
8. The compound according to claim 1, which is selected from the group consisting of:

methyl (3-[4-(2-amino-2-oxoethyl)piperazin-1-yl]-4-{[(2-phenyl-1,3-thiazol-4-yl)carbonyl]amino}phenyl)acetate, N-[2-(3-carbamoylpyrrolidin-1-yl)phenyl]-2-phenyl-1,3-thiazole-4-carboxamide, N-{2-[4-(2-amino-2-oxoethyl)piperazin-1-yl]phenyl}-2-morpholin-4-yl-1,3-thiazole-4-carboxamide, N-{2-[4-(2-amino-2-oxoethyl)piperazin-1-yl]-3-fluorophenyl}-2-(4-hydroxypiperidin-1-yl)-1,3-thiazole-4-carboxamide, N-{2-[4-(2-amino-2-oxoethyl)piperazin-1-yl]phenyl}-2-[(2-methoxyethyl)(methyl)amino]-1,3-thiazole-4-carboxamide, 1-{3-[({2-[(2-methoxyethyl)(methyl)amino]-1,3-thiazol-4-yl}carbonyl)amino]pyridin-2-yl}piperidine-4-carboxamide, N-{2-[4-(2-amino-2-oxoethyl)piperazin-1-yl]pyridin-3-yl}-2-[(2-methoxyethyl)(methyl)amino]-1,3-thiazole-4-carboxamide, N-[2-(4-hydroxypiperidin-1-yl)phenyl]-2-phenyl-1,3-oxazole-4-carboxamide, 1-(2-{[(2-morpholin-4-yl-1,3-oxazol-4-yl)carbonyl]amino}phenyl)piperidine-4-carboxamide, 1-(3-{[(2-morpholin-4-yl-1,3-oxazol-4-yl)carbonyl]amino}pyridin-2-yl)piperidine-4-carboxamide, and N-{2-[4-(2-amino-2-oxoethyl)piperazin-1-yl]phenyl}-2-(3-furyl)-1,3-oxazole-4-carboxamide or a salt thereof.
9. A pharmaceutical composition, comprising the azolecarboxamide derivative according to claim 1 or a pharmaceutically acceptable salt thereof, as an active ingredient.
10. An agent for treating or preventing disease related to NGF or trkA receptor, comprising the azolecarboxamide derivative according to claim 1 or a pharmaceutically acceptable salt thereof, as an active ingredient.
11. An agent for treating or preventing urinary frequency, urinary urgency, urinary incontinence, lower urinary tract pain, which are associated with various lower urinary tract diseases, or various diseases accompanied by pain, which comprises the azolecarboxamide derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.
12. The prophylactic or therapeutic agent according to Claim 9, wherein the lower urinary tract disease is overactive bladder, interstitial cystitis or chronic prostatitis.
13. The prophylactic or therapeutic agent according to claim 9, wherein the disease accompanied by pain is osteoarthritis.
14. A method for treating or preventing urinary frequency, urinary urgency, urinary incontinence, lower urinary tract pain, which are associated with various lower urinary tract diseases, or various diseases accompanied by a pain, which comprises administrating an effective amount of the azolecarboxamide derivative according to claim 1 or a pharmaceutically acceptable salt thereof to a patient.
15. A trkA receptor inhibitor, comprising the azolecarboxamide derivative according to claim 1 or a pharmaceutically acceptable salt thereof.
CA2649043A 2006-04-19 2007-04-19 Azolecarboxamide derivative Expired - Fee Related CA2649043C (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
JP2006-115481 2006-04-19
JP2006115481 2006-04-19
PCT/JP2007/059009 WO2007123269A1 (en) 2006-04-19 2007-04-19 Azolecarboxamide derivative

Publications (2)

Publication Number Publication Date
CA2649043A1 true CA2649043A1 (en) 2007-11-01
CA2649043C CA2649043C (en) 2013-09-17

Family

ID=38625159

Family Applications (1)

Application Number Title Priority Date Filing Date
CA2649043A Expired - Fee Related CA2649043C (en) 2006-04-19 2007-04-19 Azolecarboxamide derivative

Country Status (9)

Country Link
US (1) US8163746B2 (en)
EP (1) EP2009005A4 (en)
JP (1) JP5182088B2 (en)
KR (1) KR20090004976A (en)
CN (1) CN101426774B (en)
CA (1) CA2649043C (en)
MX (1) MX2008013400A (en)
TW (1) TW200808788A (en)
WO (1) WO2007123269A1 (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009109576A1 (en) * 2008-03-03 2009-09-11 Novartis Ag Pim kinase inhibitors and methods of their use
WO2010059606A2 (en) * 2008-11-19 2010-05-27 Schering Corporation Inhibitors of diacylglycerol acyltransferase
WO2010059611A2 (en) * 2008-11-19 2010-05-27 Schering Corporation Inhibitors of diacylglycerol acyltransferase
WO2010059602A3 (en) * 2008-11-19 2010-07-15 Schering Corporation Inhibitors of diacylglycerol acyltransferase
US8168794B2 (en) 2008-03-03 2012-05-01 Novartis Ag Pim kinase inhibitors and methods of their use
US8987457B2 (en) 2012-05-21 2015-03-24 Novartis Ag Ring-substituted N-pyridinyl amides as kinase inhibitors

Families Citing this family (44)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8318735B2 (en) * 2006-10-31 2012-11-27 Merck Sharp & Dohme Corp. 2-aminothiazole-4-carboxylic amides as protein kinase inhibitors
US9206142B2 (en) 2006-10-31 2015-12-08 Merck Sharp & Dohme Corp. Anilinopiperazine derivatives and methods of use thereof
MX2009004785A (en) * 2006-10-31 2009-06-05 Schering Corp 2-aminothiazole-4-carboxylic amides as protein kinase inhibitors.
CA2701946A1 (en) * 2007-10-11 2009-04-16 Vertex Pharmaceuticals Incorporated Heteroaryl amides useful as inhibitors of voltage-gated sodium channels
EP2206707B1 (en) * 2007-10-24 2014-07-23 Astellas Pharma Inc. Azolecarboxamide compound or salt thereof
WO2009058739A1 (en) * 2007-10-29 2009-05-07 Schering Corporation Heterocyclic urea and thiourea derivatives and methods of use thereof
MX2010004876A (en) * 2007-10-29 2010-07-28 Schering Corp Diamido thiazole derivatives as protein kinase inhibitors.
MX2010004875A (en) * 2007-10-29 2010-05-19 Schering Corp Thiazole derivatives as protein kinase inhibitors.
EP2070916A1 (en) * 2007-12-10 2009-06-17 Bayer Schering Pharma Aktiengesellschaft 2-Arylthiazol-4-carboxylic acid derivatives, their manufacture and use as medicine
EP2292089A1 (en) 2008-01-11 2011-03-09 Astellas Pharma Inc. Model animal having both pain in testis or testis-related discomfort actions and frequent urination
GB0818241D0 (en) 2008-10-06 2008-11-12 Cancer Res Technology Compounds and their use
EP2370445B1 (en) * 2008-12-03 2014-07-23 The Scripps Research Institute Stem cell cultures
UY32481A (en) 2009-03-10 2010-09-30 Takeda Pharmaceutical BENZOFURAN DERIVATIVES
US8362249B2 (en) * 2009-04-27 2013-01-29 Boehringer Ingelheim International Gmbh CXCR3 receptor antagonists
WO2010126811A1 (en) 2009-04-27 2010-11-04 Boehringer Ingelheim International Gmbh Cxcr3 receptor antagonists
WO2011025706A2 (en) 2009-08-26 2011-03-03 Schering Corporation Heterocyclic amide compounds as protein kinase inhibitors
US8435976B2 (en) * 2009-09-08 2013-05-07 F. Hoffmann-La Roche 4-substituted pyridin-3-yl-carboxamide compounds and methods of use
CN102625807B (en) * 2009-09-08 2016-03-09 霍夫曼-拉罗奇有限公司 Pyridin-3-yl-benzamide compound that 4-replaces and using method
US9452980B2 (en) * 2009-12-22 2016-09-27 Hoffmann-La Roche Inc. Substituted benzamides
WO2011084985A1 (en) * 2010-01-07 2011-07-14 Boehringer Ingelheim International Gmbh Cxcr3 receptor antagonists
DE102010007281A1 (en) 2010-02-08 2011-08-11 EMC microcollections GmbH, 72070 Novel aminoalkyl-oxazole and aminoalkyl-thiazolecarboxamides and their application to stimulate the endogenous regeneration of hair cells in the internal organ Corti organ in the mammal
US20130109682A1 (en) * 2010-07-06 2013-05-02 Novartis Ag Cyclic ether compounds useful as kinase inhibitors
WO2012058174A1 (en) * 2010-10-29 2012-05-03 Schering Corporation Novel thiazole-carboxamide derivatives as pdk1 inhibitors
CA2932051A1 (en) 2013-12-20 2015-06-25 Laboratorios Del Dr. Esteve, S.A. Piperazine derivatives having multimodal activity against pain
US9981942B2 (en) * 2013-12-20 2018-05-29 Laboratorios Del Dr. Esteve S.A. Piperidine derivatives having multimodal activity against pain
AU2016242973A1 (en) 2015-04-03 2017-11-23 Bristol-Myers Squibb Company Inhibitors of indoleamine 2,3-dioxygenase for the treatment of cancer
GB201518365D0 (en) * 2015-10-16 2015-12-02 Exonate Ltd Compounds
RU2018128334A (en) * 2016-02-09 2020-03-10 Инвентисбио Инк. INDOLAMIN-2,3-DIOXYGENASE INHIBITORS (IDO)
CR20180443A (en) 2016-03-17 2018-11-21 Hoffmann La Roche MORPHOLINE DERIVATIVE
GB201622362D0 (en) * 2016-12-29 2017-02-15 Medical Res Council Tech Compounds
GB201622365D0 (en) * 2016-12-29 2017-02-15 Medical Res Council Tech Compounds
DK3600312T3 (en) * 2017-03-26 2023-07-31 Takeda Pharmaceuticals Co PIPERIDINYL AND PIPERAZINYL SUBSTITUTED HETEROAROMATIC CARBOXAMIDES AS MODULATORS OF GPR6
JP2020516672A (en) * 2017-04-18 2020-06-11 セルジーン クオンティセル リサーチ，インク． Therapeutic compound
JP2020536870A (en) * 2017-10-05 2020-12-17 バイオジェン インコーポレイテッド Method for preparing alphacarboxamide pyrrolidine derivative
CN111196805A (en) * 2018-11-17 2020-05-26 曲阜德禄生物科技有限公司 Synthesis method and application of piperidyl thiazole formamide compound
CN114364798A (en) 2019-03-21 2022-04-15 欧恩科斯欧公司 Combination of Dbait molecules with kinase inhibitors for the treatment of cancer
CN113727984B (en) 2019-05-21 2024-03-15 浙江海正药业股份有限公司 Macrocyclic derivatives, preparation method and application thereof
WO2021089791A1 (en) 2019-11-08 2021-05-14 INSERM (Institut National de la Santé et de la Recherche Médicale) Methods for the treatment of cancers that have acquired resistance to kinase inhibitors
WO2021130723A1 (en) * 2019-12-24 2021-07-01 Cadila Healthcare Limited Novel compounds suitable for the treatment of dyslipidemia
AR120896A1 (en) * 2019-12-25 2022-03-30 Astellas Pharma Inc PYRIDAZINIL-THIAZOLCARBOXAMIDE COMPOUNDS AS DGKz INHIBITORS
WO2021148581A1 (en) 2020-01-22 2021-07-29 Onxeo Novel dbait molecule and its use
KR20230116838A (en) 2020-11-30 2023-08-04 아스테라스 세이야쿠 가부시키가이샤 Heteroarylcarboxyamide Compounds
WO2023170024A1 (en) * 2022-03-11 2023-09-14 University Of Copenhagen Camk2 modulators and their use in medicine
WO2024155864A1 (en) * 2023-01-20 2024-07-25 Allianthera (Suzhou) Biopharmaceutical Co., Ltd. Sprk1 inhibitors and methods of use

Family Cites Families (51)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5395932A (en) 1993-04-30 1995-03-07 G. D. Searle & Co. 2,3-,4-,5-,6-,7-,8-,9- and/or 10-substituted dibenzoxazepine compounds, pharmaceutical compositions and methods of use
GB9424379D0 (en) 1994-12-02 1995-01-18 Agrevo Uk Ltd Fungicides
WO1999000121A1 (en) 1997-06-26 1999-01-07 Eli Lilly And Company Antithrombotic agents
CA2346108A1 (en) 1998-11-09 2000-05-18 James Black Foundation Limited Gastrin and cholecystokinin receptor ligands
PT1169038E (en) 1999-04-15 2012-10-26 Bristol Myers Squibb Co Cyclic protein tyrosine kinase inhibitors
US6399780B1 (en) 1999-08-20 2002-06-04 Cephalon, Inc. Isomeric fused pyrrolocarbazoles and isoindolones
US6455525B1 (en) 1999-11-04 2002-09-24 Cephalon, Inc. Heterocyclic substituted pyrazolones
JP2001278872A (en) * 2000-03-27 2001-10-10 Banyu Pharmaceut Co Ltd New aminothiazole derivative
FR2807660A1 (en) 2000-04-13 2001-10-19 Warner Lambert Co Use of a nerve growth factor antagonist for the manufacture of a medicament for the prevention or treatment of chronic visceral pain
EP1339680A1 (en) 2000-09-01 2003-09-03 Glaxo Group Limited Substituted oxindole derivatives as tyrosine kinase inhibitors
EP1317446A1 (en) 2000-09-01 2003-06-11 Glaxo Group Limited Oxindole derivatives
HUP0303204A3 (en) 2000-11-16 2010-04-28 Sankyo Co 1-methylcarbapenem derivatives and pharmaceutical compositions containing them
AU2002248432A1 (en) 2001-02-14 2002-08-28 Sankyo Company, Limited Oxazole derivatives, their preparation and their use as cytokine inhibitors
JP2002338537A (en) 2001-05-16 2002-11-27 Mitsubishi Pharma Corp Amide compound and its medicinal use
AR034897A1 (en) 2001-08-07 2004-03-24 Hoffmann La Roche N-MONOACILATED DERIVATIVES OF O-PHENYLENDIAMINS, THEIR HETEROCICLICAL ANALOGS OF SIX MEMBERS AND THEIR USE AS PHARMACEUTICAL AGENTS
US7015231B2 (en) 2001-09-27 2006-03-21 Smithkline Beecham Corporation Chemical compounds
JP2003231687A (en) 2002-02-04 2003-08-19 Japan Tobacco Inc Pyrazolyl condensed ring compound and pharmaceutical use thereof
US20040110802A1 (en) 2002-08-23 2004-06-10 Atli Thorarensen Antibacterial benzoic acid derivatives
CA2515215A1 (en) 2003-02-10 2004-08-26 Amgen Inc. Vanilloid receptor ligands and their use in treatments
US7223788B2 (en) 2003-02-14 2007-05-29 Sanofi-Aventis Deutschland Gmbh Substituted N-aryl heterocycles, process for their preparation and their use as medicaments
DE10306250A1 (en) * 2003-02-14 2004-09-09 Aventis Pharma Deutschland Gmbh Substituted N-aryl heterocycles, processes for their preparation and their use as pharmaceuticals
EP1631560A2 (en) 2003-04-25 2006-03-08 3-Dimensional Pharmaceuticals, Inc. C-fms kinase inhibitors
US20050113566A1 (en) 2003-04-25 2005-05-26 Player Mark R. Inhibitors of C-FMS kinase
US7427683B2 (en) 2003-04-25 2008-09-23 Ortho-Mcneil Pharmaceutical, Inc. c-fms kinase inhibitors
FR2856685B1 (en) * 2003-06-25 2005-09-23 Merck Sante Sas THIAZOLYLPIPERIDINE DERIVATIVES, PROCESSES FOR PREPARING THEM AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM
WO2005030705A1 (en) 2003-09-24 2005-04-07 Methylgene, Inc. Inhibitors of histone deacetylase
TW200523252A (en) 2003-10-31 2005-07-16 Takeda Pharmaceutical Pyridine compounds
NZ547220A (en) 2003-11-14 2009-12-24 Vertex Pharma Thiazoles and oxazoles useful as modulators of ATP-binding cassette transporters
MY141220A (en) * 2003-11-17 2010-03-31 Astrazeneca Ab Pyrazole derivatives as inhibitors of receptor tyrosine kinases
JP2007522204A (en) 2004-02-11 2007-08-09 ペインセプター ファーマ コーポレーション Methods for modulating neurotrophin-mediated activity
EP1742921A2 (en) 2004-04-21 2007-01-17 AstraZeneca AB Pyrazole derivatives useful for the treatment of cancer
KR20070049655A (en) 2004-08-13 2007-05-11 제넨테크, 인크. 2-amido-thiazole-based compounds exhibiting atp-utilizing enzyme inhibitory activity, and compositions, and uses thereof
DE102004039789A1 (en) 2004-08-16 2006-03-02 Sanofi-Aventis Deutschland Gmbh Aryl-substituted polycyclic amines, process for their preparation and their use as pharmaceuticals
US7601745B2 (en) 2004-09-27 2009-10-13 4Sc Ag Heterocyclic NF-kB inhibitors
US7713973B2 (en) 2004-10-15 2010-05-11 Takeda Pharmaceutical Company Limited Kinase inhibitors
JP5008569B2 (en) * 2004-10-22 2012-08-22 ジヤンセン・フアーマシユーチカ・ナームローゼ・フエンノートシヤツプ Aromatic amides as inhibitors of C-FMS kinase
WO2006116355A1 (en) 2005-04-22 2006-11-02 Kalypsys, Inc. Ortho-terphenyl inhibitors of p38 kinase and methods of treating inflammatory disorders
KR20080019213A (en) 2005-05-09 2008-03-03 아칠리온 파르마세우티칼스 인코포레이티드 Thiazole compounds and methods of use
JP2008543965A (en) 2005-06-28 2008-12-04 タケダ・ケンブリッジ・リミテッド Heterocyclic non-peptide GNRH antagonist
PE20070211A1 (en) 2005-07-29 2007-05-12 Medivir Ab MACROCYCLIC COMPOUNDS AS INHIBITORS OF HEPATITIS C VIRUS
CN101273038A (en) 2005-07-29 2008-09-24 美迪维尔公司 Macrocylic inhibitors of hepatitis C virus
AR055203A1 (en) 2005-08-31 2007-08-08 Otsuka Pharma Co Ltd BENZOTIOPHENE DERIVATIVES WITH ANTIPSYTICAL PROPERTIES
EP1926719B1 (en) 2005-09-13 2017-05-31 Janssen Pharmaceutica NV 2-aniline-4-aryl substituted thiazole derivatives
US20110028462A1 (en) 2005-09-20 2011-02-03 Colletti Steven L Niacin Receptor Agonists, compositions Containing Such Compounds and Methods of Treatment
ES2572263T3 (en) 2005-10-25 2016-05-31 Shionogi & Co Dihydrooxazine and tetrahydropyrimidine derivatives as BACE 1 inhibitors
BRPI0619052A2 (en) * 2005-11-28 2011-09-20 Hoffmann La Roche compounds, process for their preparation, pharmaceutical compositions comprising them, method for the therapeutic and / or prophylactic treatment of diseases that are modulated by diacylglycerol acyltransferase inhibitors, and their use
JP2009529059A (en) 2006-03-08 2009-08-13 アキリオン ファーマシューティカルズ，インコーポレーテッド Substituted aminothiazole derivatives having anti-hepatitis C virus activity
EP1881001A1 (en) 2006-07-20 2008-01-23 Tibotec Pharmaceuticals Ltd. HCV NS-3 serine protease inhibitors
US8318735B2 (en) 2006-10-31 2012-11-27 Merck Sharp & Dohme Corp. 2-aminothiazole-4-carboxylic amides as protein kinase inhibitors
MX2009004785A (en) 2006-10-31 2009-06-05 Schering Corp 2-aminothiazole-4-carboxylic amides as protein kinase inhibitors.
US9206142B2 (en) 2006-10-31 2015-12-08 Merck Sharp & Dohme Corp. Anilinopiperazine derivatives and methods of use thereof

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009109576A1 (en) * 2008-03-03 2009-09-11 Novartis Ag Pim kinase inhibitors and methods of their use
US8168794B2 (en) 2008-03-03 2012-05-01 Novartis Ag Pim kinase inhibitors and methods of their use
US8829193B2 (en) 2008-03-03 2014-09-09 Novartis Ag PIM kinase inhibitors and methods of their use
WO2010059606A2 (en) * 2008-11-19 2010-05-27 Schering Corporation Inhibitors of diacylglycerol acyltransferase
WO2010059611A2 (en) * 2008-11-19 2010-05-27 Schering Corporation Inhibitors of diacylglycerol acyltransferase
WO2010059602A3 (en) * 2008-11-19 2010-07-15 Schering Corporation Inhibitors of diacylglycerol acyltransferase
WO2010059606A3 (en) * 2008-11-19 2010-09-16 Schering Corporation Inhibitors of diacylglycerol acyltransferase
WO2010059611A3 (en) * 2008-11-19 2010-11-18 Schering Corporation Inhibitors of diacylglycerol acyltransferase
CN102282138A (en) * 2008-11-19 2011-12-14 先灵公司 Inhibitors of diacylglycerol acyltransferase
US8716312B2 (en) 2008-11-19 2014-05-06 Merck Sharp & Dohme Corporation Inhibitors of diacylglycerol acyltransferase
US8987457B2 (en) 2012-05-21 2015-03-24 Novartis Ag Ring-substituted N-pyridinyl amides as kinase inhibitors
US9173883B2 (en) 2012-05-21 2015-11-03 Novartis Ag Ring-substituted N-pyridinyl amides as kinase inhibitors

Also Published As

Publication number Publication date
CA2649043C (en) 2013-09-17
KR20090004976A (en) 2009-01-12
TW200808788A (en) 2008-02-16
US20090286766A1 (en) 2009-11-19
CN101426774A (en) 2009-05-06
EP2009005A4 (en) 2010-06-02
JP5182088B2 (en) 2013-04-10
WO2007123269A1 (en) 2007-11-01
EP2009005A1 (en) 2008-12-31
JPWO2007123269A1 (en) 2009-09-10
MX2008013400A (en) 2008-11-10
US8163746B2 (en) 2012-04-24
CN101426774B (en) 2012-04-25

Similar Documents

Publication Publication Date Title
CA2649043A1 (en) Azolecarboxamide derivative
JP5321467B2 (en) Azole carboxamide compound or salt thereof
AU2017237930B2 (en) Allosteric modulators of nicotinic acetylcholine receptors
EP3377060A1 (en) Pyrazole compounds and methods of making and using same
NZ551017A (en) Substituted 2-quinolyl-oxazoles useful as PDE4 inhibitors
JP6452703B2 (en) WNT pathway modulator
JP5357884B2 (en) Benzothiazoles as ghrelin receptor modulators
JP2021522253A (en) Compounds and their use
MX2011005233A (en) Inhibitors of diacylglycerol acyltransferase.
JP2023529884A (en) COLLAGEN 1 TRANSLATION INHIBITOR AND METHOD OF USE THEREOF
JP2010254641A (en) Azole carboxamide compound or salt thereof
NZ785933A (en) Allosteric modulators of nicotinic acetylcholine receptors
EA035585B1 (en) Allosteric modulators of nicotinic acetylcholine receptors
NZ723972B2 (en) Hepatitis b core protein allosteric modulators
KR20090007675A (en) Triazole derivatives having antifungal activity, method for the preparation thereof and pharmaceutical composition containing same

Legal Events

Date Code Title Description
EEER Examination request
MKLA Lapsed

Effective date: 20150420